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1. SPEN induces miR-4652-3p to target HIPK2 in nasopharyngeal carcinoma

Author

Liyang Wu, Yan Huang, Xiong Liu, Zhen Liu, Guifang Yu, Liu Yang, Yingying Hu, Yang Li, Chao Cheng, Xingyu Tao, Jingjing He, Shu Liu, Qingping Jiang, Yumin Lv, Yun Su, and Yuting Ma

Subjects
Male, 0301 basic medicine, Cancer Research, Proto-Oncogene Proteins c-jun, Immunology, Repressor, Protein Serine-Threonine Kinases, Biology, Article, law.invention, Metastasis, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cell Movement, law, Cell Line, Tumor, medicine, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, lcsh:QH573-671, Protein kinase A, Protein kinase B, PI3K/AKT/mTOR pathway, Cancer, Gene knockdown, Nasopharyngeal Carcinoma, lcsh:Cytology, RNA-Binding Proteins, Cell Biology, Middle Aged, Prognosis, medicine.disease, Cell invasion, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, MicroRNAs, 030104 developmental biology, Nasopharyngeal carcinoma, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Cancer research, Suppressor, Female, Carrier Proteins, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

SPEN family transcriptional repressor (SPEN), also known as the SMART/HDAC1-associated repressor protein (SHARP), has been reported to modulate the malignant phenotypes of breast cancer, colon cancer, and ovarian cancer. However, its role and the detail molecular basis in nasopharyngeal carcinoma (NPC) remain elusive. In this study, the SPEN mRNA and protein expression was found to be increased in NPC cells and tissues compared with nonmalignant nasopharyngeal epithelial cells and tissues. Elevated SPEN protein expression was found to promote the pathogenesis of NPC and lead to poor prognosis. Knockdown of SPEN expression resulted in inactivation ofPI3K/AKT and c-JUN signaling, thereby suppressing NPC migration and invasion. In addition, miR-4652-3p was found to be a downstream inducer of SPEN by targeting the homeodomain interacting protein kinase 2 (HIPK2) gene, a potential tumor suppressor that reduces the activation of epithelial–mesenchymal transition (EMT) signaling, thereby reducing its expression and leading to increased NPC migration, invasion, and metastasis. In addition, SPEN was found to induce miR-4652-3p expression by activating PI3K/AKT/c-JUN signaling to target HIPK2. Our data provided a new molecular mechanism for SPEN as a metastasis promoter through activation of PI3K/AKT signaling, thereby stimulating the c-JUN/miR-4652-3p axis to target HIPK2 in NPC.

Published
2020

2. Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity

Author

Zhiming Shao, Jin Ye, Yi Huang, Wei Jiang, Tengchuan Jin, Yongping Cai, Suling Liu, Yize Hao, Yueyin Pan, Yi-Zhou Jiang, Yunzhi Wang, Yuting Ma, Menghao Dong, Qingqing Li, Lei Song, Benjie Shan, Hongqi Li, Li Bai, Huafeng Zhang, Guido Kroemer, Hualong Lin, Rongbin Zhou, Huanyu Wang, Chen Ding, and Chao Wang

Subjects
0303 health sciences, Chemotherapy, Myeloid, biology, business.industry, medicine.medical_treatment, Phosphatase, Cancer, Inflammasome, Cell Biology, medicine.disease, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Immune system, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Medicine, Phosphorylation, PTEN, business, 030304 developmental biology, medicine.drug
Abstract

PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3-ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1β restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1β production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.

Published
2020

4. Genetic and molecular control of grain yield in maize

Author

Yantian Lu, Guoying Wang, Yuting Ma, Junjie Fu, and Hongwei Zhang

Subjects
0106 biological sciences, 0301 basic medicine, Genetics, Plant physiology, Single-nucleotide polymorphism, Plant Science, Molecular control, Biology, Quantitative trait locus, 01 natural sciences, Article, 03 medical and health sciences, 030104 developmental biology, Plant species, Grain yield, Association mapping, Agronomy and Crop Science, Molecular Biology, Gene, 010606 plant biology & botany, Biotechnology
Abstract

Understanding the genetic and molecular basis of grain yield is important for maize improvement. Here, we identified 49 consensus quantitative trait loci (cQTL) controlling maize yield-related traits using QTL meta-analysis. Then, we collected yield-related traits associated SNPs detected by association mapping and identified 17 consensus significant loci. Comparing the physical positions of cQTL with those of significant SNPs revealed that 47 significant SNPs were located within 20 cQTL regions. Furthermore, intensive reviews of 31 genes regulating maize yield-related traits found that the functions of many genes were conservative in maize and other plant species. The functional conservation indicated that some of the 575 maize genes (orthologous to 247 genes controlling yield or seed traits in other plant species) might be functionally related to maize yield-related traits, especially the 49 maize orthologous genes in cQTL regions, and 41 orthologous genes close to the physical positions of significant SNPs. In the end, we prospected on the integration of the public sources for exploring the genetic and molecular mechanisms of maize yield-related traits, and on the utilization of genetic and molecular mechanisms for maize improvement. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11032-021-01214-3.

Published
2021

5. Growth differentiation factor 11: a 'rejuvenation factor' involved in regulation of age-related diseases?

Author

Yuting Ma, Hongyan Qiu, Xiaodong Sun, Junfeng Shi, Ningning Hou, Yongping Liu, Fang Han, and Na Huang

Subjects
Senescence, Aging, Sarcopenia, growth differentiation factor 11, transforming growth factor, Longevity, Review, Biology, Mice, Alzheimer Disease, age-related diseases, medicine, Animals, Humans, Rejuvenation, Muscle Strength, Muscle, Skeletal, Pathological, Cellular Senescence, Regeneration (biology), Skeletal muscle, Cell Biology, Recombinant Proteins, Growth Differentiation Factors, Stroke, Disease Models, Animal, medicine.anatomical_structure, Cardiovascular Diseases, regeneration, GDF11, Bone Morphogenetic Proteins, Cell aging, Neuroscience, Transforming growth factor, Signal Transduction
Abstract

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β superfamily of cytokines, is a critical rejuvenation factor in aging cells. GDF11 improves neurodegenerative and neurovascular disease outcomes, increases skeletal muscle volume, and enhances muscle strength. Its wide-ranging biological effects may include the reversal of senescence in clinical applications, as well as the ability to reverse age-related pathological changes and regulate organ regeneration after injury. Nevertheless, recent data have led to controversy regarding the functional roles of GDF11, because the underlying mechanisms were not clearly established in previous studies. In this review, we examine the literature regarding GDF11 in age-related diseases and discuss potential mechanisms underlying the effects of GDF11 in regulation of age-related diseases.

Published
2020

6. Quorum Quenching Mediated Bacteria Interruption as a Probable Strategy for Drinking Water Treatment against Bacterial Pollution

Author

Xiaohui Sun, Jia Liu, Shu-Feng Zhou, Yuting Ma, Junyi Zhang, and Changan Xu

Subjects
bacteria interruption, Health, Toxicology and Mutagenesis, lcsh:Medicine, Bacillus, medicine.disease_cause, Article, Water Purification, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, Pyocyanin, Lactonase, medicine, 030304 developmental biology, 0303 health sciences, Bacteria, biology, 030306 microbiology, Chemistry, Pseudomonas aeruginosa, Drinking Water, lcsh:R, Public Health, Environmental and Occupational Health, Biofilm, Rhamnolipid, Quorum Sensing, biology.organism_classification, drinking water treatment, bacteria pollution, Quorum Quenching, biology.protein, quorum quenching, Water treatment
Abstract

Pseudomonas aeruginosa in water lines may cause bacteria pollution indrinking fountains that could affect the quality of potable water, thus posing a risk to public health. A clean and efficient strategy is required for drinking water treatment for food safety. In this study, an AiiA-homologous lactonase was cloned from a deep-sea probiotics Bacillus velezensis (DH82 strain), and was heterologously expressed so that the capacity of the enzyme on the N-acyl-L-homoserine lactone (AHL)-degrading, effect of bacterial proliferation, biofilm formation and toxic factors release, and membrane pollution from P. aeruginosa could each be investigated to analyze the effect of the enzyme on water treatment. The enzyme effectively degraded the signal molecules of P. aeruginosa (C6-HSL and C12-HSL), inhibited early proliferation and biofilm formation, significantly reduced toxic products (pyocyanin and rhamnolipid), and inhibited bacterial fouling on the filter membrane, which prevented the secondary contamination of P. aeruginosa in drinking water. The findings demonstrated that the quorum quenching enzyme from probiotics could prevent bacteria pollution and improve potable water quality, and that the enzyme treatment could be used as a probable strategy for drinking water treatment.

Published
2020

7. Identification of Potential Indicators for Survival in Patients With Thyroid Cancer Based on Mrna Expression Levels of Family With Sequence Similarity 3 Members

Author

Junfeng Shi, Hongyan Qiu, Yuting Ma, Yongping Liu, Fang Han, Ruiyan Pan, Xiaodong Sun, and Ningning Hou

Subjects
genetic structures, Similarity (network science), Mrna expression, medicine, In patient, Identification (biology), Computational biology, Biology, medicine.disease, Thyroid cancer, Sequence (medicine)
Abstract

Background: Thyroid cancer (THCA) is a common head and neck malignancy. The family with sequence similarity 3 (FAM3) is a cytokine-like gene family with four members, which is presumed to participate in the development of many cancer types. However, the expression patterns of FAM3s in THCA and their prognostic values, have not yet been established. Methods: We investigated differential expressions of FAM3 mRNA and protein in THCA, then validated the findings for FAM3B by immunohistochemistry. We also investigated survival data with respect to FAM3 expression patterns in patients with THCA. FAM3s information regarding their relationships with clinical pathological parameters were obtained and FAM3 mutations were assessed. KEGG and GO pathway regarding FAM3C were obtained using online databases. To investigate potential correlations between FAM3s and immune cell infiltration, we investigated the roles of FAM3s in immune cells of patients with THCA. Results: The mRNA expression of FAM3C were significantly elevated in THCA tissues; high expression levels of FAM3C protein were also observed in THCA tissues. A significant association between the pathological stage and the expression of FAM3C was found in patients with THCA. Patients with THCA who had high mRNA expression levels of FAM3C exhibited significantly more favourable prognosis, compared with patients who had low mRNA expression levels of FAM3C. Conclusions: Overall, FAM3C may play vital roles in the pathogenesis and development of THCA, and these findings constitute novel insights for biomarkers of immunotherapeutic targeted agents and may aid in the identification of prognostic biomarkers for THCA.

Published
2020

8. Lipid-mediated regulation of the cancer-immune crosstalk

Author

Shuqing Zhang, Yuting Ma, Minxin Shi, and Ziqi Jin

Subjects
0301 basic medicine, Pharmacology, Tumor microenvironment, Stromal cell, Cell, Lipid metabolism, Cell Communication, Biology, Lipid Metabolism, Cell biology, 03 medical and health sciences, Crosstalk (biology), 030104 developmental biology, 0302 clinical medicine, Immune system, medicine.anatomical_structure, Immunity, 030220 oncology & carcinogenesis, Neoplasms, Cancer cell, medicine, Tumor Microenvironment, Animals, Humans, Signal Transduction
Abstract

Besides acting as principle cellular building blocks and energy reservoirs, lipids also carry important signals associated with many fundamental cell biological processes, such as proliferation, differentiation, migration, stress responses and cell demise. Hyperactive lipid metabolism is closely associated with cancer progression and unfavorable outcomes. The underlying mechanisms are being gradually deciphered. In this review, we aim to summarize recent advances on how reprogrammed lipid metabolism and accompanying signaling cascades directly modulate cancer cells, as well as influencing stromal cells and immune cells within the tumor microenvironment. For future studies, special attention should be paid to lipid-mediated crosstalk among cancer cells, their neighboring stromal cells, and immune cells, plus how these multi-level communications determine anti-tumor immunity and bring novel immunotherapeutic opportunities.

Published
2020

9. Phagocytosis of Candida albicans Inhibits Autophagic Flux in Macrophages

Author

Jianbo Tong, Qing Chen, Zhimin Duan, Xu Chen, Song Xu, Leilei Du, Min Li, Yuting Ma, and Rong Zeng

Subjects
0301 basic medicine, Aging, Article Subject, Phagocytosis, Vacuole, Biochemistry, Mice, 03 medical and health sciences, Candida albicans, Autophagy, Animals, lcsh:QH573-671, Phagosome, biology, lcsh:Cytology, Chemistry, Macrophages, Colocalization, Cell Biology, General Medicine, biology.organism_classification, Corpus albicans, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, embryonic structures, biological phenomena, cell phenomena, and immunity, Flux (metabolism), Research Article
Abstract

Autophagy machinery has roles in the defense against microorganisms such as Candida albicans. Lipidated LC3, the marker protein of autophagy, participates in the elimination of C. albicans by forming a single-membrane phagosome; this process is called LC3-associated phagocytosis (LAP). However, the influence of C. albicans on autophagic flux is not clear. In this study, we found that C. albicans inhibited LC3 turnover in macrophages. After the phagocytosis of C. albicans in macrophages, we observed fewer acridine orange-positive vacuoles and RFP-GFP-LC3 puncta without colocalization with phagocytized C. albicans. However, phagocytosis of C. albicans led to LC3 recruitment, but p62 and ATG9A did not colocalize with LC3 or C. albicans. These effects are due to an MTOR-independent pathway. Nevertheless, we found that the C. albicans pattern-associated molecular pattern β-glucan increased LC3 turnover. In addition, phagocytosis of C. albicans caused a decrease in BrdU incorporation. Blocking autophagic flux aggravated this effect. Our findings suggest that phagocytosis of C. albicans decreases autophagic flux but induces LAP in an MTOR-independent manner in macrophages. Occupation of LC3 by recruiting engulfed C. albicans might contribute to the inhibition of autophagic flux. Our study highlights the coordinated machinery between canonical autophagy and LAP that defends against C. albicans challenge.

Published
2018

10. The renaissance of anti-neoplastic immunity from tumor cell demise

Author

Yuting Ma, Heng Yang, Qingqing Li, and Jonathan M. Pitt

Subjects
0301 basic medicine, Programmed cell death, Necroptosis, Immunology, Biology, Cancer Vaccines, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, Antigens, Neoplasm, Neoplasms, Autophagy, Tumor Microenvironment, Immunology and Allergy, Animals, Humans, Immunologic Surveillance, Tumor microenvironment, Cell Death, Pyroptosis, Pattern recognition receptor, 030104 developmental biology, 030220 oncology & carcinogenesis, Receptors, Pattern Recognition, Immunogenic cell death, DNA Damage
Abstract

Cancer therapies can temporarily reduce tumor burdens by inducing malignant cell death. However, cancer cure is still far from realization because tumors often gain resistance to current treatment and eventually relapse. Accumulating evidence suggests that successful cancer interventions require anti-tumor immunity. Therapy-induced cell stress responses ultimately result in one or more cell death modalities, including apoptosis, autophagy, necroptosis, and pyroptosis. These irreversible dying processes are accompanied by active or passive release of cell death-associated molecular patterns (CDAMPs), which can be sensed by corresponding pattern recognition receptors (PRR) on tumor-infiltrating immune cells. This crosstalk with the immune system can reawaken immune surveillance in the tumor microenvironment (TME). This review focuses on immune-modulatory properties of anti-cancer regimens and CDAMP-mediated communications between cell stress responses and the immune contexture of TME. In addition, we describe how immunogenic cell death can elicit strong and durable anti-tumor immune responses.

Published
2017

11. CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy

Author

Antonella Sistigu, Sandy Adjemian, João Paulo Portela Catani, Gautier Stoll, Laetitia Aymeric, Heng Yang, Lorenzo Galluzzi, Dalil Hannani, Yuting Ma, Joachim L. Schultze, Helene Duret, Stephen R. Mattarollo, Guido Kroemer, Laurence Zitvogel, Oliver Kepp, Michele W.L. Teng, Mark J. Smyth, Yidan Wang, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose, cancer et immunité (U848), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris 1 Panthéon-Sorbonne - UFR Histoire (UP1 UFR09), Université Paris 1 Panthéon-Sorbonne (UP1), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Cancer Institute Regina Elena [Rome, Italy], Life and Medical Sciences Institute for Genomics and Immunoregulation, University of Bonn, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11), Université Paris 1 Panthéon-Sorbonne - École d'Histoire (UP1 UFR09), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Bonn = University of Bonn, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Panthéon-Sorbonne - UFR Histoire (UP1 UFR09), Université Panthéon-Sorbonne (UP1), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, and MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cancer Research, Chemokine, Anthracycline, Receptors, CCR2, T-Lymphocytes, Antigen presentation, Antigen-Presenting Cells, Antineoplastic Agents, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Lymphocyte Activation, Mice, Immune system, Antigen, Antigens, Neoplasm, Cell Line, Tumor, Neoplasms, Animals, Medicine, Anthracyclines, Antigen-presenting cell, Chemokine CCL2, ComputingMilieux_MISCELLANEOUS, Oligonucleotide Array Sequence Analysis, Antigen Presentation, biology, business.industry, Dendritic Cells, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Dendritic cell, Flow Cytometry, 3. Good health, Mice, Inbred C57BL, Lymphatic system, Microscopy, Fluorescence, Oncology, Immunology, Cancer research, biology.protein, Lymph Node Excision, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business, Neoplasm Transplantation, Signal Transduction
Abstract

The therapeutic efficacy of anthracyclines relies, at least partially, on the induction of a dendritic cell– and T-lymphocyte–dependent anticancer immune response. Here, we show that anthracycline-based chemotherapy promotes the recruitment of functional CD11b+CD11c+Ly6ChighLy6G−MHCII+ dendritic cell–like antigen-presenting cells (APC) into the tumor bed, but not into lymphoid organs. Accordingly, draining lymph nodes turned out to be dispensable for the proliferation of tumor antigen–specific T cells within neoplastic lesions as induced by anthracyclines. In addition, we found that tumors treated with anthracyclines manifest increased expression levels of the chemokine Ccl2. Such a response is important as neoplasms growing in Ccl2−/− mice failed to accumulate dendritic cell–like APCs in response to chemotherapy. Moreover, cancers developing in mice lacking Ccl2 or its receptor (Ccr2) exhibited suboptimal therapeutic responses to anthracycline-based chemotherapy. Altogether, our results underscore the importance of the CCL2/CCR2 signaling axis for therapeutic anticancer immune responses as elicited by immunogenic chemotherapy. Cancer Res; 74(2); 436–45. ©2013 AACR.

Published
2014

12. Autophagy and Cellular Immune Responses

Author

Yuting Ma, Lorenzo Galluzzi, Guido Kroemer, and Laurence Zitvogel

Subjects
Immunity, Cellular, Programmed cell death, Cellular immunity, Innate immune system, Myeloid, T-Lymphocytes, Immunology, Autophagy, Antigen-Presenting Cells, Biology, Cell biology, Immunosurveillance, Infectious Diseases, Immune system, medicine.anatomical_structure, Immunity, Neoplasms, medicine, Animals, Cytokines, Humans, Immunology and Allergy, Myeloid Cells, Lysosomes
Abstract

Autophagy constitutes a mechanism for the sequestration and lysosomal degradation of various cytoplasmic structures, including damaged organelles and invading microorganisms. Autophagy not only represents an essential cell-intrinsic mechanism to protect against internal and external stress conditions but also shapes cellular immunity. Recent evidence indicates that autophagic responses in antigen-donor cells affect the release of several cytokines and "danger signals." Thus, especially when it precedes cell death, autophagy alerts innate immune effectors to elicit cognate immune responses. Autophagy is also important for the differentiation, survival, and activation of myeloid and lymphoid cells. Accordingly, inherited mutations in autophagy-relevant genes are associated with immune diseases, whereas oncogenesis-associated autophagic defects promote the escape of developing tumors from immunosurveillance. Here, we discuss the regulation of autophagy in the course of cellular immune responses and emphasize its impact on the immunogenicity of antigen-donor cells and on the activity of antigen-presenting cells and T lymphocytes.

Published
2013

13. Anticancer Chemotherapy-Induced Intratumoral Recruitment and Differentiation of Antigen-Presenting Cells

Author

Dalil Hannani, Yuting Ma, Erika Vacchelli, Mickaël Michaud, Frédéric Schlemmer, Eric Solary, Laetitia Aymeric, Guido Kroemer, Oliver Kepp, Lorenzo Galluzzi, Laurie Menger, Laurence Zitvogel, Nathalie Droin, Helene Duret, Sandy Adjemian, Takahiro Yamazaki, Heng Yang, Isabelle Martins, Siamon Gordon, Kim Steegh, Mark J. Smyth, Roman Krzysiek, João Paulo Portela Catani, Abdul Qader Sukkurwala, Stephen R. Mattarollo, Philip R. Taylor, Peter van Endert, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose, cancer et immunité (U848), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris 1 Panthéon-Sorbonne - UFR Histoire (UP1 UFR09), Université Paris 1 Panthéon-Sorbonne (UP1), Bio-Indicateurs Actuels et Fossiles (BIAF), Université d'Angers (UA), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches Juridiques de l'Université de Franche-Comté - UFC (EA 3225) (CRJFC), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut Gustave Roussy (IGR), Service de microbiologie, immunologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sir William Dunn School of Pathology [Oxford], University of Oxford [Oxford], Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université Panthéon-Sorbonne - UFR Histoire (UP1 UFR09), Université Panthéon-Sorbonne (UP1), Département de Géologie, Laboratoire d'étude des bio-indicateurs actuels et fossiles EA2644, École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Franche-Comté (UFC), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Université Paris 1 Panthéon-Sorbonne - École d'Histoire (UP1 UFR09), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches Juridiques de l'Université de Franche-Comté - UFC (UR 3225) (CRJFC), and University of Oxford

Subjects
Adoptive cell transfer, Antigen presentation, Immunology, Antigen-Presenting Cells, Antineoplastic Agents, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Monocyte-Macrophage Precursor Cells, Mice, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, Antigen, Antigens, Neoplasm, Cell Movement, Nucleotidases, Cell Line, Tumor, Animals, Antigens, Ly, Medicine, Immunology and Allergy, Anthracyclines, Granulocyte Precursor Cells, IL-2 receptor, Antigen-presenting cell, 030304 developmental biology, Immunity, Cellular, 0303 health sciences, CD11b Antigen, CD40, biology, business.industry, Receptors, Purinergic, Cell Differentiation, Dendritic Cells, Neoplasms, Experimental, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Adoptive Transfer, CD11c Antigen, 3. Good health, Mice, Inbred C57BL, Infectious Diseases, 030220 oncology & carcinogenesis, biology.protein, Interleukin 12, [SDV.IMM]Life Sciences [q-bio]/Immunology, business
Abstract

International audience; The therapeutic efficacy of anthracyclines relies on antitumor immune responses elicited by dying cancer cells. How chemotherapy-induced cell death leads to efficient antigen presentation to T cells, however, remains a conundrum. We found that intra-tumoral CD11c + CD11b + Ly6C hi cells, which displayed some characteristics of inflammatory dendritic cells and included granulomonocytic precursors, were crucial for anthracycline-induced anticancer immune responses. ATP released by dying cancer cells recruited myeloid cells into tumors and stimulated the local differentiation of CD11c + CD11b + Ly6C hi cells. Such cells efficiently engulfed tumor antigens in situ and presented them to T lymphocytes, thus vaccinating mice, upon adoptive transfer, against a challenge with cancer cells. Manipulations preventing tumor infiltration by CD11c + CD11b + Ly6C hi cells, such as the local overexpression of ectonu-cleotidases, the blockade of purinergic receptors, or the neutralization of CD11b, abolished the immune system-dependent antitumor activity of anthracyclines. Our results identify a subset of tumor-infiltrating leukocytes as therapy-relevant antigen-presenting cells.

Published
2013
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14. Yet another pattern recognition receptor involved in the chemotherapy-induced anticancer immune response: Formyl peptide receptor-1

Author

Guido Kroemer, Elisa E. Baracco, Yuting Ma, Erika Vacchelli, and Laurence Zitvogel

Subjects
0301 basic medicine, Immunology, Purinergic receptor, Pattern recognition receptor, Immune receptor, Biology, Formyl peptide receptor 1, Cell biology, Immunosurveillance, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immune system, Oncology, 030220 oncology & carcinogenesis, Cancer research, Immunology and Allergy, Immunogenic cell death, Receptor, Author's View
Abstract

Several pattern recognition receptors including toll-like receptors and purinergic receptors are implicated in the anticancer immune response elicited by anthracyclines or oxaliplatin. Recently, formyl peptide receptor-1 (FPR1) has been involved in this response as well. FPR1 is required for the correct positioning of dendritic cells (DC) close to dying cancer cells. A genetic defect in FPR1 abrogates cross-presentation of tumor antigens by DC, thereby compromising therapy-elicited immunosurveillance.

Published
2016

15. Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

Author

Guido Kroemer, Yuting Ma, Oliver Kepp, Sylvie Souquere, Allan Sauvat, Guo Chen, Heng Yang, Federico Pietrocola, Heng Zhou, Laurence Zitvogel, Takahiro Yamazaki, Erika Vacchelli, Christophe Klein, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tsinghua University [Beijing] (THU), Université Paris Descartes - Paris 5 (UPD5), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Tsinghua University [Beijing], Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, biology, Kinase, Necroptosis, [SDV]Life Sciences [q-bio], Immunology, HMGB1, 3. Good health, Cell biology, Immunosurveillance, 03 medical and health sciences, 030104 developmental biology, Immune system, Oncology, Cancer cell, Cancer research, biology.protein, Immunology and Allergy, Cytotoxic T cell, Immunogenic cell death, ComputingMilieux_MISCELLANEOUS, Original Research
Abstract

Chemotherapy can reinstate anticancer immunosurveillance through inducing tumor immunogenic cell death (ICD). Here, we show that anthracyclines and oxaliplatin can trigger necroptosis in murine cancer cell lines expressing receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL). Necroptotic cells featured biochemical hallmarks of ICD and stimulated anticancer immune responses in vivo. Chemotherapy normally killed Rip3 (-/-) and Mlkl (-/-) tumor cells and normally induced caspase-3 activation in such cells, yet was unable to reduce their growth in vivo. RIP3 or MLKL deficiency abolished the capacity of dying cancer cells to elicit an immune response. This could be attributed to reduced release of ATP and high mobility group box 1 (HMGB1) by RIP3 and MLKL-deficient cells. Measures designed to compensate for deficient ATP and HMGB1 signaling restored the chemotherapeutic response of Rip3 (-/-) and Mlkl (-/-) cancers. Altogether, these results suggest that RIP3 and MLKL can contribute to ICD signaling and tumor immunogenicity.

Published
2016

17. The oncolytic peptide LTX-315 triggers immunogenic cell death

Author

Allan Sauvat, Laura Senovilla, Peng Liu, Kevin Müller, Laurence Zitvogel, Sabrina Forveille, Takahiro Yamazaki, Yuting Ma, Lucillia Bezu, Heng Zhou, Guido Kroemer, Oliver Kepp, Huijun Yang, Øystein Rekdal, Institut Gustave Roussy (IGR), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11), Université Paris Descartes - Paris 5 (UPD5), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Rétrovirus endogènes et éléments rétroides des eucaryotes supérieurs (REERES (UMR 8122)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Suzhou University, Chinese Academy of Sciences [Changchun Branch] (CAS), Université Pierre et Marie Curie - Paris 6 (UPMC), Lytix Biopharma, University of Tromsø (UiT), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska University Hospital [Stockholm], Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), HAL UPMC, Gestionnaire, Institut Gustave Roussy ( IGR ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ), Université Paris Descartes - Paris 5 ( UPD5 ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Rétrovirus endogènes et éléments rétroides des eucaryotes supérieurs ( REERES (UMR 8122) ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Chinese Academy of Sciences [Changchun Branch] ( CAS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), University of Tromsø ( UiT ), and Hôpital Européen Georges Pompidou [APHP] ( HEGP )

Subjects
0301 basic medicine, Cancer Research, Programmed cell death, T-Lymphocytes, Immunology, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Cellular and Molecular Neuroscience, Bcl-2-associated X protein, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Interferon, Cell Line, Tumor, Neoplasms, medicine, Humans, bcl-2-Associated X Protein, Immunity, Cellular, Cell Death, biology, business.industry, [ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710, Cell Biology, Molecular biology, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710, 3. Good health, bcl-2 Homologous Antagonist-Killer Protein, 030104 developmental biology, Cell culture, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cancer cell, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Immunogenic cell death, Original Article, business, Oligopeptides, Calreticulin, medicine.drug
Abstract

Published version. Source at http://dx.doi.org/10.1038/cddis.2016.47 LTX-315 is a cationic amphilytic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/ BAK1-regulated, caspase-independent necrosis. Based on the observation that intratumorally injected LTX-315 stimulates a strong T lymphocyte-mediated anticancer immune response, we investigated whether LTX-315 may elicit the hallmarks of immunogenic cell death (ICD), namely (i) exposure of calreticulin on the plasma membrane surface, (ii) release of ATP into the extracellular space, (iii) exodus of HMGB1 from the nucleus, and (iv) induction of a type-1 interferon response. Using a panel of biosensor cell lines and robotized fluorescence microscopy coupled to automatic image analysis, we observed that LTX-315 induces all known ICD characteristics. This conclusion was validated by several independent methods including immunofluorescence stainings (for calreticulin), bioluminescence assays (for ATP), immunoassays (for HMGB1), and RT-PCRs (for type-1 interferon induction). When injected into established cancers, LTX-315 caused a transiently hemorrhagic focal necrosis that was accompanied by massive release of HMGB1 (from close-to-all cancer cells), as well as caspase-3 activation in a fraction of the cells. LTX-315 was at least as efficient as the positive control, the anthracycline mitoxantrone (MTX), in inducing local inflammation with infiltration by myeloid cells and T lymphocytes. Collectively, these results support the idea that LTX-315 can induce ICD, hence explaining its capacity to mediate immune-dependent therapeutic effects.

Published
2016

18. The dendritic cell–tumor cross-talk in cancer

Author

Yuting Ma, Clara Locher, Laurence Zitvogel, Guido Kroemer, and Laetitia Aymeric

Subjects
Antigen Presentation, Tumor microenvironment, T-Lymphocytes, Immunology, Antigen presentation, Cancer, Gene targeting, Dendritic Cells, Dendritic cell, Biology, medicine.disease, Immunity, Innate, Cross-Priming, Immune system, Immunity, Neoplasms, medicine, Animals, Humans, Immunology and Allergy, Antigen-presenting cell, Neuroscience
Abstract

The question as to whether the tumor grows because of or despite the host immune system is being progressively addressed with refined technology, gene targeting in mice and human translational research. The productive interplay between major actors of the antitumor immunity is actively compromised by the tumor microenvironment subverting the links between innate and cognate immunity and/or generating devastating new players. The complexity of the host-tumor equilibrium could be dissected at the reduced level of the dialogue between professional antigen presenting cells (APC), more precisely dendritic cells, and tumor cells that may profoundly dictate the outcome of the neoplasma. This review will summarize the novel mechanisms by which tumor cells regulate DC recruitment, differentiation, activation and cross-presenting functions in tumor beds and how innate players might counterbalance these interactions. Finally, we will highlight interesting strategies that harness the DC potential to fight against cancer.

Published
2011

19. Desirable cell death during anticancer chemotherapy

Author

Yuting Ma, François Ghiringhelli, Rosa Conforti, Yannis Morel, Takahiro Yamazaki, Sylvie Rusakiewicz, Clara Locher, Laurence Zitvogel, Antoine Tesniere, Lionel Apetoh, Guido Kroemer, Laetitia Aymeric, and Jean-Philippe Girard

Subjects
Toll-like receptor, Chemotherapy, General Neuroscience, medicine.medical_treatment, T cell, Immunogenicity, Immunotherapy, Biology, General Biochemistry, Genetics and Molecular Biology, Immune system, medicine.anatomical_structure, History and Philosophy of Science, Immunology, medicine, Cytotoxic T cell, Immunogenic cell death
Abstract

The concept of immunogenic chemotherapy that has recently emerged relies upon the capacity of a cytotoxic compound to trigger a cell-death modality. This modality elicits cross-priming by dendritic cells of tumor antigen-specific T cells that will contribute to the tumoricidal activity of the compound and protect the host against relapse. In contrast, most anticancer drugs elicit nonimmunogenic apoptosis that is not accompanied with an immunizing property. This review will discuss some molecular and metabolic changes required at the level of the tumor that must engage key pathways at the level of the host for the induction of Tc1 polarized–protective T cell responses during chemotherapy. We will summarize the immune adjuvants that can boost the immunogenicity of cell death to augment the efficacy of chemotherapy.

Published
2010

20. CD2AP is indispensable to multistep cytotoxic process by NK cells

Author

Wei Feng, Dongfang Liu, Jing Qi, Ping Xiong, Yuting Ma, Guoying Zheng, Yong Xu, Min Fang, Zheng Tan, Feili Gong, Heng Yang, Pan Li, and Fang Zheng

Subjects
Fas Ligand Protein, T cell, Immunology, Receptors, Antigen, T-Cell, Biology, Jurkat Cells, Interleukin 21, Membrane Microdomains, medicine, Humans, Cytotoxic T cell, Molecular Biology, Lipid raft, Adaptor Proteins, Signal Transducing, Secretory Vesicles, Degranulation, Actin remodeling, Cell biology, Killer Cells, Natural, Cytoskeletal Proteins, Cell killing, medicine.anatomical_structure, Gene Knockdown Techniques, K562 Cells, Cytokinesis, HeLa Cells
Abstract

CD2-associated protein (CD2AP) is a cytoplasmic protein which localizes to membrane ruffles, lipid rafts and the leading edges of cells. It is implicated in podocyte homeostasis, signal transduction, dynamic actin remodeling and also membrane trafficking during endocytosis and cytokinesis. CD2AP was reported to orchestrate receptor patterning and cytoskeletal polarity in T cell contacts and it could also modulate TCR signaling. However, whether it plays a role in NK cell killing remains unknown. In this study, we discovered that interfering with CD2AP expression strongly reduced cytotoxicity of human NK92 cell line and this effect was independent of FasL sensitivity of target cells. Conjugate formation and degranulation were impeded in NK92 cells after CD2AP knockdown. Upon encountering target cells, CD2AP in NK92 is enriched near contact site and colocalizes with FasL-bearing granules. In contrast, FasL-bearing granules were found rarely polarized toward cell contact site after CD2AP knockdown. Furthermore, by immunoprecipitation from NK92 cell lysates and transient expression studies in 293T and Hela cells, we demonstrated that CD2AP associates with FasL. Thus, CD2AP, through facilitating conjugate formation and directed transport of lytic granules, plays an important role in NK cells killing.

Published
2010

21. Therapy-induced microenvironmental changes in cancer

Author

Yuting Ma, Jonathan M. Pitt, Laurence Zitvogel, Guido Kroemer, and Heng Yang

Subjects
0301 basic medicine, Necroptosis, Biology, medicine.disease_cause, Immunomodulation, 03 medical and health sciences, Immune system, Stress, Physiological, Neoplasms, Drug Discovery, Antineoplastic Combined Chemotherapy Protocols, medicine, Tumor Microenvironment, Animals, Humans, Genetics (clinical), Inflammation, Tumor microenvironment, Cell Death, Radiotherapy, Autophagy, Cancer, medicine.disease, Combined Modality Therapy, Cell biology, 030104 developmental biology, Cell Transformation, Neoplastic, Immune System, Cancer cell, Unfolded protein response, Disease Progression, Molecular Medicine, Carcinogenesis
Abstract

In the past decade, the focus of tumor biology research has been switching from the functional dissection of oncogenes and tumor suppressor genes to investigation of the cross-talk between tumor cells and their microenvironment. Tumorigenesis requires the organized assembly of cancer cells with non-malignant cells and non-cellular stroma, resembling an abnormal organogenesis. This process can be modulated by local cellular stress responses, such as senescence, ER stress and autophagy, and inflammatory and immunosuppressive cells and effector molecules within the tumor microenvironment (TME). Various cellular stress responses and cell death modalities are triggered in response to chemotherapies, radiotherapies, and targeted therapies (including immunotherapies). The exposure of immunostimulatory factors could (re)awaken anti-tumor immunity. Unexpectedly, the gut microbial flora is becoming recognized as an important external modulator of the TME. We will discuss in detail the TME changes that take place after certain cancer therapies, highlighting the importance of cellular stress responses, tumor-infiltrating immune cells, and microbiota-derived factors.

Published
2015

22. STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells

Author

Yuting Ma, Federico Pietrocola, Laurence Zitvogel, Takahiro Yamazaki, Heng Yang, Guido Kroemer, and Heng Zhou

Subjects
STAT3 Transcription Factor, Transcriptional Activation, Cancer Research, Chemokine, Receptors, CXCR3, Fibrosarcoma, Mice, Nude, Receptor, Interferon alpha-beta, CXCR3, Chemokine CXCL9, Mice, Immune system, Lymphocytes, Tumor-Infiltrating, Interferon, Cell Line, Tumor, medicine, Cytotoxic T cell, CXCL10, Animals, Mice, Inbred BALB C, Antibiotics, Antineoplastic, biology, Drug Synergism, Dendritic Cells, Combined Modality Therapy, Cyclic S-Oxides, Neoplasm Proteins, Chemokine CXCL10, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Oncology, Doxorubicin, Cancer cell, Interferon Type I, Cancer research, biology.protein, CXCL9, Female, Colorectal Neoplasms, Immunocompetence, medicine.drug, Signal Transduction, T-Lymphocytes, Cytotoxic
Abstract

STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3−/− cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell–dependent and T lymphocyte–mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3−/− cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3Y705F) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3−/− cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3−/− and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells. Cancer Res; 75(18); 3812–22. ©2015 AACR.

Published
2015

23. Anticancer activity of cardiac glycosides

Author

Laurie Menger, Mickaël Michaud, Erika Vacchelli, Guido Kroemer, Yuting Ma, Lorenzo Galluzzi, Oliver Kepp, Isabelle Martins, Laurence Zitvogel, Abdul Qader Sukkurwala, and Sandy Adjemian

Subjects
Na+/K+ ATPase, Digoxin, Digitoxin, Immunology, Pharmacology, HMGB1, calreticulin, Immune system, immunogenic cell death, medicine, Carcinoma, Immunology and Allergy, Author's View, biology, business.industry, digoxin, medicine.disease, Oncology, Cancer cell, biology.protein, Immunogenic cell death, business, digitoxin, Calreticulin, medicine.drug
Abstract

Retrospective clinical data indicate that cardiac glycosides (CGs), notably digoxin, prolong the survival of carcinoma patients treated with conventional chemotherapy. CGs are known to influence the immune response at multiple levels. In addition, recent results suggest that CGs trigger the immunogenic demise of cancer cells, an effect that most likely contributes to their clinical anticancer activity.

Published
2012

24. Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy

Author

Aicha Goubar, Julien Adam, Joanna Cyrta, Kariman Chaba, Mireia Niso-Santano, Valentina La Sorsa, Laurence Zitvogel, Christina Pfirschke, Guido Kroemer, Gilles Uzé, Oliver Kepp, Magali Lacroix-Triki, Francesca Urbani, Antonella Sistigu, Elisa E. Baracco, Suzette Delaloge, Sylvain Ladoire, David Enot, Camilla Engblom, Marco Bianchi, Laurent Arnould, Virginie Quidville, Mauro Delorenzi, Enrico Proietti, Melvyn T. Chow, Laetitia Aymeric, Fabrice Andre, Giovanna Ziccheddu, Joachim L. Schultze, Alexander M.M. Eggermont, Thomas Tüting, Laetitia Fend, Mark J. Smyth, Catarina Remédios, Takahiro Yamazaki, Robert D. Schreiber, Laura Bracci, Erika Vacchelli, Rosa Conforti, Ilio Vitale, Paola Sestili, Mikael J. Pittet, Marie Charlotte Dessoliers, Filippo Belardelli, Vichnou Poirier-Colame, Frédérique Penault-Llorca, Jean Philippe Spano, Lajos Pusztai, Xavier Préville, Dalil Hannani, Yuting Ma, National Cancer Institute Regina Elena [Rome, Italy], Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Institut Gustave Roussy (IGR), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Département de biologie et pathologie médicales [Gustave Roussy], Apoptose, cancer et immunité (U848), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Life and Medical Sciences Institute for Genomics and Immunoregulation, Universität Bonn = University of Bonn, Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Breast Medical Oncology [Houston], The University of Texas M.D. Anderson Cancer Center [Houston], Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], UNICANCER-UNICANCER, Harvard Medical School [Boston] (HMS), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Cell Biology and Neurosciences, Université Paris-Sud - Paris 11 (UP11), Sistigu, A, Yamazaki, T, Vacchelli, E, Chaba, K, Enot, Dp, Adam, J, Vitale, I, Goubar, A, Baracco, Ee, Remédios, C, Fend, L, Hannani, D, Aymeric, L, Ma, Y, Niso Santano, M, Kepp, O, Schultze, Jl, Tüting, T, Belardelli, F, Bracci, L, La Sorsa, V, Ziccheddu, G, Sestili, P, Urbani, F, Delorenzi, M, Lacroix Triki, M, Quidville, V, Conforti, R, Spano, Jp, Pusztai, L, Poirier Colame, V, Delaloge, S, Penault Llorca, F, Ladoire, S, Arnould, L, Cyrta, J, Dessoliers, Mc, Eggermont, A, Bianchi, MARCO EMILIO, Pittet, M, Engblom, C, Pfirschke, C, Préville, X, Uzè, G, Schreiber, Rd, Chow, Mt, Smyth, Mj, Proietti, E, André, F, Kroemer, G, Zitvogel, L., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), University of Bonn, Istituto Superiore di Sanità, Service d'Oncologie médicale [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Istituto Superiore di Sanita', and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Myxovirus Resistance Proteins, Messenger, Receptor, Interferon alpha-beta, Inbred C57BL, chemotherapy, Interferon alpha-beta, Mice, Interferon, Receptors, Anthracyclines, Neoplasm Metastasis, RIG-I, Pattern recognition receptor, Adaptor Proteins, General Medicine, Neoadjuvant Therapy, 3. Good health, Gene Expression Regulation, Neoplastic, Treatment Outcome, Receptors, Pattern Recognition, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunocompetence, medicine.drug, Receptor, Signal Transduction, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pattern Recognition, Settore BIO/09, General Biochemistry, Genetics and Molecular Biology, Paracrine signalling, Immune system, medicine, CXCL10, Animals, Humans, cancer, RNA, Messenger, Autocrine signalling, Neoplastic, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Toll-Like Receptor 3, Mice, Inbred C57BL, Vesicular Transport, Chemokine CXCL10, Adaptor Proteins, Vesicular Transport, Gene Expression Regulation, Doxorubicin, Immunology, TLR3, RNA
Abstract

International audience; The immune system is routinely confronted with cell death resulting from the physiological turnover of renewable tissues, as well as from pathological insults of several types. We hypothesize the existence of a mechanism that allows the immune system to discriminate between physiological and pathological instances of cell death, but the factors that determine whether cellular demise is perceived as a neutral, tolerogenic or immunogenic event remain unclear 1. Infectious insults are accompanied by so-called microbe-associated molecular patterns (MAMPs), i.e., viral or bacterial products that activate immune cells through a panel of pattern-recognition receptors (PRRs) 2. Moreover, intracellular pathogens generally trigger adaptive mechanisms aimed toward the re-establishment of homeosta-sis, including the unfolded protein response (UPR) and autophagy 3,4. In mammals, MAMPs coupled to the activation of stress responses Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN- and IFN- receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy. npg

Published
2014

25. Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8

Author

Michael Durchschlag, Lorenzo Galluzzi, Frank Madeo, Mickaël Michaud, L Zitvogel, Laura Senovilla, E Sulpice, Erika Vacchelli, Frédéric Schlemmer, Yuting Ma, Antonella Sistigu, Christoph Ruckenstuhl, Isabelle Martins, Abdul Qader Sukkurwala, Guido Kroemer, Oliver Kepp, Wang Y, Xavier Gidrol, Schlumberger, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Princeton University, Institut Gustave Roussy (IGR), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
musculoskeletal diseases, Chemokine, Saccharomyces cerevisiae Proteins, [SDV]Life Sciences [q-bio], Chemokine CXCL2, Antineoplastic Agents, Apoptosis, Saccharomyces cerevisiae, Receptors, Interleukin-8B, Receptors, Interleukin-8A, Mice, Immune system, Cell Line, Tumor, Neoplasms, Animals, Humans, CXC chemokine receptors, Autocrine signalling, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Original Paper, Mice, Inbred BALB C, biology, Interleukin-8, Dendritic Cells, Cell Biology, HCT116 Cells, Cell biology, Mice, Inbred C57BL, CXCL2, Cancer cell, biology.protein, Mitoxantrone, Signal transduction, Calreticulin, Transcriptome, HeLa Cells, Signal Transduction
Abstract

The exposure of calreticulin (CRT) on the surface of stressed and dying cancer cells facilitates their uptake by dendritic cells and the subsequent presentation of tumor-associated antigens to T lymphocytes, hence stimulating an anticancer immune response. The chemotherapeutic agent mitoxantrone (MTX) can stimulate the peripheral relocation of CRT in both human and yeast cells, suggesting that the CRT exposure pathway is phylogenetically conserved. Here, we show that pheromones can act as physiological inducers of CRT exposure in yeast cells, thereby facilitating the formation of mating conjugates, and that a large-spectrum inhibitor of G protein-coupled receptors (which resemble the yeast pheromone receptor) prevents CRT exposure in human cancer cells exposed to MTX. An RNA interference screen as well as transcriptome analyses revealed that chemokines, in particular human CXCL8 (best known as interleukin-8) and its mouse ortholog Cxcl2, are involved in the immunogenic translocation of CRT to the outer leaflet of the plasma membrane. MTX stimulated the production of CXCL8 by human cancer cells in vitro and that of Cxcl2 by murine tumors in vivo. The knockdown of CXCL8/Cxcl2 receptors (CXCR1/Cxcr1 and Cxcr2) reduced MTX-induced CRT exposure in both human and murine cancer cells, as well as the capacity of the latter-on exposure to MTX-to elicit an anticancer immune response in vivo. Conversely, the addition of exogenous Cxcl2 increased the immunogenicity of dying cells in a CRT-dependent manner. Altogether, these results identify autocrine and paracrine chemokine signaling circuitries that modulate CRT exposure and the immunogenicity of cell death.

Published
2014

26. Chemokines and chemokine receptors required for optimal responses to anticancer chemotherapy

Author

Sandy Adjemian, Lorenzo Galluzzi, Guido Kroemer, Laurence Zitvogel, and Yuting Ma

Subjects
CCR1, cancer stem cells, autophagy, biology, Chemokine receptor CCR5, business.industry, γδ T lymphocytes, Immunology, immunosurveillance, C-C chemokine receptor type 6, ATP, Chemokine receptor, Oncology, immunogenic cell death, biology.protein, Immunology and Allergy, Medicine, CXCL10, CXC chemokine receptors, business, CCL13, Author's View, CCL21
Abstract

Depending on tumor type, stage and immunological contexture, the inhibition of chemokines or their receptors may yield positive or deleterious effects on disease progression. We have recently demonstrated in several murine models of anthracycline-based chemotherapy that the inhibition of chemokine (C-C motif) ligand 2 (CCL2) or chemokine (C-C motif) receptor 2 (CCR2) may impair the elicitation of anticancer immune responses that contribute to therapeutic success.

Published
2014

27. Autophagy-dependent ATP release from dying cells via lysosomal exocytosis

Author

Yuting Ma, Guido Kroemer, Oliver Kepp, Isabelle Martins, Lorenzo Galluzzi, and Yidan Wang

Subjects
LAMP1, Autophagy, ATG5, Apoptosis, Nerve Tissue Proteins, Cell Biology, Pannexin, Biology, Exocytosis, Cell biology, Adenosine Triphosphate, Biochemistry, Lysosomal-Associated Membrane Protein 1, Extracellular, Immunogenic cell death, V-ATPase, Animals, Humans, Secretion, Molecular Biology
Abstract

ATP not only represents a key molecule for the intracellular storage and utilization of energy, but also plays a central role in the extracellular milieu, as it both recruits and activates immune cells. The secretion of ATP in the course of immunogenic cell death (ICD), a peculiar type of apoptosis that elicits adaptive immune responses, critically relies on the molecular machinery for autophagy. We have recently demonstrated that autophagy allows for the ICD-associated secretion of ATP as it contributes to the maintenance of lysosomal ATP stores. In addition, we found that ATP release in this setting is mediated by a molecular mechanism that involves lysosomal-associated membrane protein 1 (LAMP1)- and pannexin 1 (PANX1)-dependent lysosomal exocytosis.

Published
2013

28. ATP-dependent recruitment, survival and differentiation of dendritic cell precursors in the tumor bed after anticancer chemotherapy

Author

Laurence Zitvogel, Abdul Qader Sukkurwala, Isabelle Martins, Mickaël Michaud, Heng Yang, Sandy Adjemian, Guido Kroemer, João Paulo Portela Catani, Oliver Kepp, Erika Vacchelli, Dalil Hannani, Yuting Ma, Lorenzo Galluzzi, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Cell Biology [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Apoptose, cancer et immunité (U848), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
autophagy, [SDV]Life Sciences [q-bio], Immunology, education, [SDV.CAN]Life Sciences [q-bio]/Cancer, doxorubicin, calreticulin, Antigen, immunogenic cell death, Extracellular, Immunology and Allergy, Medicine, Doxorubicin, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Author's View, CD39, biology, business.industry, Autophagy, apoptosis, Dendritic cell, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Oncology, Apoptosis, biology.protein, Cancer research, Immunogenic cell death, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Calreticulin, medicine.drug
Abstract

International audience; Tumor cells succumb to chemotherapy while releasing ATP. We have found that extracellular ATP attracts dendritic cell (DC) precursors into the tumor bed, facilitates their permanence in the proximity of dying cells and promotes their differentiation into mature DCs endowed with the capacity of presenting tumor-associated antigens.

Published
2013

29. Molecular mechanisms of ATP secretion during immunogenic cell death

Author

Isabelle Martins, Mickaël Michaud, Yuting Ma, Abdul Qader Sukkurwala, J-L Perfettini, Shensi Shen, Wang Y, Laurence Zitvogel, Guido Kroemer, Oliver Kepp, Lorenzo Galluzzi, and Didier Métivier

Subjects
Programmed cell death, Antineoplastic Agents, Nerve Tissue Proteins, Connexins, Autophagy-Related Protein 5, Mice, Adenosine Triphosphate, Lysosomal-Associated Membrane Protein 1, Cell Line, Tumor, Animals, Humans, Secretion, HMGB1 Protein, RNA, Small Interfering, Molecular Biology, Caspase, Myosin Type II, rho-Associated Kinases, Original Paper, biology, LAMP1, Cell Death, Autophagy, Cell Membrane, RNA-Binding Proteins, Cell Biology, Cell biology, DNA-Binding Proteins, Apoptosis, biology.protein, Immunogenic cell death, RNA Interference, Lysosomes, Microtubule-Associated Proteins
Abstract

The immunogenic demise of cancer cells can be induced by various chemotherapeutics, such as anthracyclines and oxaliplatin, and provokes an immune response against tumor-associated antigens. Thus, immunogenic cell death (ICD)-inducing antineoplastic agents stimulate a tumor-specific immune response that determines the long-term success of therapy. The release of ATP from dying cells constitutes one of the three major hallmarks of ICD and occurs independently of the two others, namely, the pre-apoptotic exposure of calreticulin on the cell surface and the postmortem release of high-mobility group box 1 (HMBG1) into the extracellular space. Pre-mortem autophagy is known to be required for the ICD-associated secretion of ATP, implying that autophagy-deficient cancer cells fail to elicit therapy-relevant immune responses in vivo. However, the precise molecular mechanisms whereby ATP is actively secreted in the course of ICD remain elusive. Using a combination of pharmacological screens, silencing experiments and techniques to monitor the subcellular localization of ATP, we show here that, in response to ICD inducers, ATP redistributes from lysosomes to autolysosomes and is secreted by a mechanism that requires the lysosomal protein LAMP1, which translocates to the plasma membrane in a strictly caspase-dependent manner. The secretion of ATP additionally involves the caspase-dependent activation of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1)-mediated, myosin II-dependent cellular blebbing, as well as the opening of pannexin 1 (PANX1) channels, which is also triggered by caspases. Of note, although autophagy and LAMP1 fail to influence PANX1 channel opening, PANX1 is required for the ICD-associated translocation of LAMP1 to the plasma membrane. Altogether, these findings suggest that caspase- and PANX1-dependent lysosomal exocytosis has an essential role in ATP release as triggered by immunogenic chemotherapy.

Published
2013

30. [Effect of Lycium ruthenicum anthocyanins on atherosclerosis in mice]

Author

Li Lin, Hai-Ying Lv, Yiping Qian, Yuting Ma, and Jin Li

Subjects
Male, medicine.medical_specialty, Lycium ruthenicum, Hypercholesterolemia, Blood lipids, Anthocyanins, chemistry.chemical_compound, Mice, Drug control, Internal medicine, medicine, Animals, Pharmacology (medical), General Pharmacology, Toxicology and Pharmaceutics, chemistry.chemical_classification, Lipoprotein lipase, Glutathione Peroxidase, Triglyceride, biology, Glutathione peroxidase, Body Weight, Lycium, biology.organism_classification, Malondialdehyde, Atherosclerosis, Lipids, Endocrinology, Complementary and alternative medicine, chemistry, Biochemistry, Liver, Simvastatin, lipids (amino acids, peptides, and proteins), medicine.drug, Phytotherapy
Abstract

OBJECTIVE: To study the effect of Lycium ruthenicum anthocyanins on atherosclerosis (AS) in mice. METHOD: Normal mice were taken as the control group, and hyperlipemia mice were divided into the model group, Lycium ruthenicum anthocyanins low, medium and high dose groups, and the simvastatin drug control group. After the oral administration, blood lipid indicators were detected by enzymatic analysis. The histomorphological changes in aortas, hearts and livers were observed, and liver-related indicators were determined by using hematoxylin-eosin (HE) staining. RESULT: Compared with the high-fat group, L. ruthenicum anthocyanins low, medium and high dose groups showed significant decrease in total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and atherosclerotic index (AI) (P < 0.05). However, high-density lipoprotein cholesterol (HDL-C) level showed a trend of higher than the model group. Liver's total antioxidant capacity (T-AOC), Glutathione peroxidase (GSH-PX), lipoprotein lipase (LPL) were significantly increased (P < 0.05), malondialdehyde (MDA) was markedly decreased (P < 0.01); the percentage of aortic plaque area of each anthocyanins dose group in the total area was significantly lower than the model group (P < 0.05); severity of aorta, heart and liver were significantly lighter than the high-fat group. But the media dose group was similar with the simvastatin group. CONCLUSION: L. ruthenicum anthocyanins can interfere the formation of AS, while lowering blood lipid levels in mice.

Published
2012

31. Cardiac Glycosides Exert Anticancer Effects by Inducing Immunogenic Cell Death

Author

Laurie Menger, Lorenzo Galluzzi, Xavier Gidrol, Mickaël Michaud, Erika Vacchelli, Grégoire Mignot, Yuting Ma, Eric Sulpice, François Ghiringhelli, Nazanine Modjtahedi, Fabrice Andre, Frédéric Schlemmer, Clara Locher, Guido Kroemer, Takahiro Yamazaki, Oliver Kepp, Isabelle Martins, Sandy Adjemian, Laurence Zitvogel, Shensi Shen, Abdul Qader Sukkurwala, Laboratoire Réactions et Génie des Procédés (LRGP), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Lecor-Esitpa, DAM Île-de-France (DAM/DIF), Direction des Applications Militaires (DAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier de Meaux, Biomicrotechnologie et génomique fonctionnelle (BIOMICS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Radiothérapie moléculaire (UMR 1030), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose, cancer et immunité (U848), Centre de Thermique de Lyon (CETHIL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Programmed cell death, Digoxin, Organoplatinum Compounds, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Biosensing Techniques, Biology, Pharmacology, Cardiac Glycosides, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, Anthracyclines, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Chemotherapy, General Medicine, medicine.disease, 3. Good health, Oxaliplatin, Cell culture, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cancer cell, Immunogenic cell death, medicine.drug
Abstract

Some successful chemotherapeutics, notably anthracyclines and oxaliplatin, induce a type of cell stress and death that is immunogenic, hence converting the patient's dying cancer cells into a vaccine that stimulates antitumor immune responses. By means of a fluorescence microscopy platform that allows for the automated detection of the biochemical hallmarks of such a peculiar cell death modality, we identified cardiac glycosides (CGs) as exceptionally efficient inducers of immunogenic cell death, an effect that was associated with the in- hibition of the plasma membrane Na + - and K + -dependent adenosine triphosphatase (Na + /K + -ATPase). CGs ex- acerbated the antineoplastic effects of DNA-damaging agents in immunocompetent but not immunodeficient mice. Moreover, cancer cells succumbing to a combination of chemotherapy plus CGs could vaccinate synge- neic mice against a subsequent challenge with living cells of the same type. Finally, retrospective clinical analy- ses revealed that the administration of the CG digoxin during chemotherapy had a positive impact on overall survival in cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma patients, especially when they were treated with agents other than anthracyclines and oxaliplatin.

Published
2012

32. Premortem autophagy determines the immunogenicity of chemotherapy-induced cancer cell death

Author

Isabelle Martins, Mickaël Michaud, Laurie Menger, Guido Kroemer, Oliver Kepp, Erika Vacchelli, Abdul Qader Sukkurwala, Yuting Ma, Sandy Adjemian, Shensi Shen, Laurence Zitvogel, and Lorenzo Galluzzi

Subjects
Necrosis, T-Lymphocytes, Antineoplastic Agents, Cell Biology, BECN1, Dendritic Cells, Biology, Models, Biological, Immunosurveillance, Mice, Immune system, Adenosine Triphosphate, Apoptosis, Gene Knockdown Techniques, Neoplasms, Cancer cell, medicine, Cancer research, Autophagy, Immunogenic cell death, Animals, Humans, Secretion, medicine.symptom, Molecular Biology
Abstract

One particular strategy to render anticancer therapies efficient consists of converting the patient's own tumor cells into therapeutic vaccines, via the induction of immunogenic cell death (ICD). One of the hallmarks of ICD dwells in the active release of ATP by cells committed to undergo, but not yet having succumbed to, apoptosis. We observed that the knockdown of essential autophagy-related genes (ATG3, ATG5, ATG7 and BECN1) abolishes the pre-apoptotic secretion of ATP by several human and murine cancer cell lines undergoing ICD. Accordingly, autophagy-competent, but not autophagy-deficient, tumor cells treated with ICD inducers in vitro could induce a tumor-specific immune response in vivo. Cancer cell lines stably depleted of ATG5 or ATG7 normally generate tumors in vivo, and such autophagy-deficient neoplasms, upon systemic treatment with ICD inducers, exhibit the same levels of apoptosis (as monitored by nuclear shrinkage and caspase-3 activation) and necrosis (as determined by following the kinetics of HMGB1 release) as their autophagy-proficient counterparts. However, autophagy-incompetent cancers fail to release ATP, to recruit immune effectors into the tumor bed and to respond to chemotherapy in conditions in which autophagy-competent tumors do so. The intratumoral administration of ecto-ATPase inhibitors increases extracellular ATP concentrations, re-establishes the therapy-induced recruitment of dendritic cells and T cells into the tumor bed, and restores the chemotherapeutic response of autophagy-deficient cancers. Altogether, these results suggest that autophagy-incompetent tumor cells escape from chemotherapy-induced (and perhaps natural?) immunosurveillance because they are unable to release ATP.

Published
2012

33. Contribution of IL-17-producing {gamma}{delta} T cells to the efficacy of anticancer chemotherapy

Author

Laurent Boucontet, Laetitia Aymeric, Noelia Casares, Yuting Ma, Guido Kroemer, Nathalie Chaput, Nicolas Ibrahim, Laurence Zitvogel, Clara Locher, Goro Matsuzaki, Bernard Ryffel, Lionel Apetoh, Juan José Lasarte, François Ghiringhelli, Kamel Benlagha, Antoine Tesniere, Julie Déchanet-Merville, Stephen R. Mattarollo, Mark J. Smyth, Pablo Pereira, Nicolas F. Delahaye, Koichi Ikuta, Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Ecole doctorale de cancérologie, Université Paris-Sud - Paris 11 ( UP11 ), Cancer immunology program, Peter MacCallum Cancer Centre, Développement des Lymphocytes, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Division of Hepatology and Gene Therapy ( CIMA ), Center for Applied Medical Research [Plamplona] ( CIMA ), Universidad de Navarra [Pamplona] ( UNAV ) -Universidad de Navarra [Pamplona] ( UNAV ), Molecular Microbiology Group ( COMB ), University of the Ruykyus, Laboratory of Biological protection, Kyoto University [Kyoto], Immunologie et Embryologie Moléculaire ( IEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Immunologie, génétique et traitement des maladies métaboliques et du diabète ( UMR_S 561 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Apoptose, cancer et immunité ( U848 ), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy ( IGR ), Composantes innées de la réponse immunitaire et différenciation ( CIRID ), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), School of Medicine, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11), Peter MacCallum Cancer Center, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Division of Hepatology and Gene Therapy (CIMA), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV)-Universidad de Navarra [Pamplona] (UNAV), Molecular Microbiology Group (COMB), Kyoto University, Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose, cancer et immunité (U848), Institut Gustave Roussy (IGR), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Vougny, Marie-Christine, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adoptive cell transfer, MESH : Aged, MESH : Equipment Design, CD8-Positive T-Lymphocytes, MESH: Catheterization, Interleukin-23, MESH: Long-Term Care, Mice, 0302 clinical medicine, MESH : Catheterization, T-Lymphocyte Subsets, MESH: Nursing, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Interferon gamma, MESH: Quality of Health Care, MESH: Professional Review Organizations, MESH: Aged, MESH : Gels, 0303 health sciences, Mice, Inbred BALB C, Cell Death, Interleukin-17, MESH : Methylene Blue, MESH : Quality of Health Care, Receptors, Antigen, T-Cell, gamma-delta, Chemotherapy regimen, MESH: Transplantation, Autologous, 3. Good health, MESH: Cosmetic Techniques, Treatment Outcome, medicine.anatomical_structure, MESH : Cadaver, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunogenic cell death, Sarcoma, Experimental, Interleukin 17, MESH : Dissection, MESH : Long-Term Care, MESH: Nursing Care, MESH: Adipose Tissue, medicine.drug, Signal Transduction, MESH : Transplantation, Autologous, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : Feasibility Studies, MESH: Gels, T cell, MESH : Male, Immunology, MESH: Dissection, Antineoplastic Agents, Biology, MESH : Nursing, MESH : Adipose Tissue, Article, MESH : Facial Muscles, 03 medical and health sciences, Interferon-gamma, Lymphocytes, Tumor-Infiltrating, Immune system, Antigen, Cell Line, Tumor, MESH: Patient Care Planning, medicine, MESH: Cadaver, Animals, MESH : Patient Care Planning, 030304 developmental biology, MESH: Humans, business.industry, MESH: Facial Muscles, T-cell receptor, MESH : Humans, Correction, MESH: Male, Mice, Inbred C57BL, MESH : Cosmetic Techniques, Doxorubicin, Cancer research, MESH : Nursing Care, MESH : Professional Review Organizations, business, MESH: Feasibility Studies, CD8, 030215 immunology, MESH: Methylene Blue, MESH: Equipment Design
Abstract

IL-17 production by γδ T cells is required for tumor cell infiltration by IFN-γ–producing CD8+ T cells and inhibition of tumor growth in response to anthracyclines., By triggering immunogenic cell death, some anticancer compounds, including anthracyclines and oxaliplatin, elicit tumor-specific, interferon-γ–producing CD8+ αβ T lymphocytes (Tc1 CTLs) that are pivotal for an optimal therapeutic outcome. Here, we demonstrate that chemotherapy induces a rapid and prominent invasion of interleukin (IL)-17–producing γδ (Vγ4+ and Vγ6+) T lymphocytes (γδ T17 cells) that precedes the accumulation of Tc1 CTLs within the tumor bed. In T cell receptor δ−/− or Vγ4/6−/− mice, the therapeutic efficacy of chemotherapy was compromised, no IL-17 was produced by tumor-infiltrating T cells, and Tc1 CTLs failed to invade the tumor after treatment. Although γδ T17 cells could produce both IL-17A and IL-22, the absence of a functional IL-17A–IL-17R pathway significantly reduced tumor-specific T cell responses elicited by tumor cell death, and the efficacy of chemotherapy in four independent transplantable tumor models. Adoptive transfer of γδ T cells restored the efficacy of chemotherapy in IL-17A−/− hosts. The anticancer effect of infused γδ T cells was lost when they lacked either IL-1R1 or IL-17A. Conventional helper CD4+ αβ T cells failed to produce IL-17 after chemotherapy. We conclude that γδ T17 cells play a decisive role in chemotherapy-induced anticancer immune responses.

Published
2011

34. Homeostatic defects in interleukin 18-deficient mice contribute to protection against the lethal effects of endotoxin

Author

Joseph A. Trapani, Claire L Cotterell, Shizuo Akira, Yoichiro Iwakura, Yuting Ma, Mark J. Smyth, Desiree A Anthony, Laurence Zitvogel, Daniel M. Andrews, Sally V. Watt, and Melvyn T. Chow

Subjects
Lipopolysaccharides, T cell, T-Lymphocytes, Immunology, Biology, Interleukin 21, Interferon-gamma, Mice, medicine, Immunology and Allergy, Animals, Homeostasis, Cells, Cultured, Inflammation, Mice, Knockout, Innate immune system, Lymphokine-activated killer cell, Innate lymphoid cell, Interleukin-17, Interleukin-18, Interleukin, Receptors, Antigen, T-Cell, gamma-delta, Cell Biology, Cell biology, Killer Cells, Natural, Mice, Inbred C57BL, medicine.anatomical_structure, Interleukin 15, Interleukin 12
Abstract

Toll-like receptor-4-lipopolysaccharide (LPS)-mediated inflammation is used to delineate signals involved in cross-talk between antigen-presenting cells (APCs) and lymphocytes such as natural killer (NK) cells. Following APC stimulation and cytokine release, NK cells produce interferon (IFN)-γ. High levels of LPS induce endotoxicosis, a systemic inflammatory disease in which IFN-γ causes significant morbidity and mortality. Several studies have highlighted the role of interleukin (IL)-18, IL-1β, IL-17A and IFN-γ in the development of endotoxicosis, but whether these cytokines interact with each other is yet to be determined. Our data demonstrate that IL-18 and IL-17A have important roles in NK cell IFN-γ production during endotoxicosis. Importantly, we provide the first evidence that IL-18 also has a role in IL-17A production by T-cell receptor (TCR)-δ cells. Furthermore, we demonstrate that IL-18-deficient mice have a defect in γδ T-cell homeostasis and IL-1β production, both of which can contribute to the development of disease through induction of IL-17A. These results reveal novel requirements for IL-18 in innate immune cell homeostasis and activation, demonstrating that the role of IL-18 in innate immunity occurs at a level other than activation.

Published
2011

35. Autophagy-Dependent Anticancer Immune Responses Induced by Chemotherapeutic Agents in Mice

Author

Laurie Menger, Yuting Ma, Shensi Shen, Francesco Di Virgilio, Santiago Rello-Varona, François Ghiringhelli, Guido Kroemer, Mickaël Michaud, Maximilien Tailler, Oliver Kepp, Marie Scoazec, Grégoire Mignot, Sandy Adjemian, Lorenzo Galluzzi, Patrizia Pellegatti, Erika Vacchelli, Isabelle Martins, Abdul Qader Sukkurwala, and Laurence Zitvogel

Subjects
Programmed cell death, cells, cancer, immunogenicity, calreticulin exposure, hmgb1, Antineoplastic Agents, Biology, immunogenicity, NO, Mice, chemistry.chemical_compound, Adenosine Triphosphate, Immune system, Cell Line, Tumor, Neoplasms, Autophagy, Extracellular, Animals, Humans, cancer, Mice, Inbred BALB C, Multidisciplinary, Cell Death, Immunogenicity, Dendritic Cells, Mice, Inbred C57BL, hmgb1, chemistry, Cell culture, Cancer research, Immunogenic cell death, cells, Mitoxantrone, Calreticulin, Adenosine triphosphate, calreticulin exposure
Abstract

Antineoplastic chemotherapies are particularly efficient when they elicit immunogenic cell death, thus provoking an anticancer immune response. Here we demonstrate that autophagy, which is often disabled in cancer, is dispensable for chemotherapy-induced cell death but required for its immunogenicity. In response to chemotherapy, autophagy-competent, but not autophagy-deficient, cancers attracted dendritic cells and T lymphocytes into the tumor bed. Suppression of autophagy inhibited the release of adenosine triphosphate (ATP) from dying tumor cells. Conversely, inhibition of extracellular ATP-degrading enzymes increased pericellular ATP in autophagy-deficient tumors, reestablished the recruitment of immune cells, and restored chemotherapeutic responses but only in immunocompetent hosts. Thus, autophagy is essential for the immunogenic release of ATP from dying cells, and increased extracellular ATP concentrations improve the efficacy of antineoplastic chemotherapies when autophagy is disabled.

Published
2011

36. Improvement of immunogenic chemotherapy by STAT3 inhibition

Author

Federico Pietrocola, Heng Yang, Takahiro Yamazaki, Heng Zhou, Laurence Zitvogel, Guido Kroemer, and Yuting Ma

Subjects
0301 basic medicine, Chemotherapy, biology, medicine.medical_treatment, Immunology, Pharmacology, Neutralization, Immunosurveillance, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immune system, Oncology, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, medicine, Cancer research, Immunology and Allergy, Immunogenic cell death, Cytotoxic T cell, STAT3, Author's View
Abstract

The inhibition of STAT3 may exert cell-autonomous cytotoxic and cytostatic effects, yet may also stimulate anticancer immunosurveillance through the neutralization of immunosuppressive circuitries. In addition, STAT3 inhibition in cancer cells may stimulate the type 1 interferon response elicited by anthracyclines. This pathway results in an enhanced chemotherapy-associated anticancer immune response with improved therapeutic efficacy. Hence, combination therapies that include immunogenic cell death (ICD) inducers and STAT3 inhibitors can be envisaged.

Published
2015

37. Tumor necrosis factor is dispensable for the success of immunogenic anticancer chemotherapy

Author

Mark J. Smyth, Yuting Ma, Guido Kroemer, Oliver Kepp, Laurence Zitvogel, Takahiro Yamazaki, Lorenzo Galluzzi, and Heng Yang

Subjects
Anthracycline, dendritic cell, Immunology, T cells, calreticulin, Immune system, immunogenic cell death, medicine, Immunology and Allergy, Doxorubicin, Interferon gamma, Original Research, interferon γ, biology, business.industry, apoptosis, Dendritic cell, Oncology, biology.protein, Cancer research, Immunogenic cell death, Tumor necrosis factor alpha, Antibody, business, medicine.drug
Abstract

The antineoplastic effects of anthracyclines have been shown to rely, at least in part, on a local immune response that involves dendritic cells (DCs) and several distinct subsets of T lymphocytes. Here, we show that the administration of anthracyclines to mice bearing established neoplasms stimulates the intratumoral secretion of tumor necrosis factor α (TNFα). However, blocking the TNFα/TNF receptor (TNFR) system by three different strategies—namely, (1) neutralizing antibodies, (2) etanercept, a recombinant protein in which TNFR is fused to the constant domain of an IgG1 molecule, and (3) gene knockout—failed to negatively affect the therapeutic efficacy of anthracyclines in three distinct tumor models. In particular, TNFα-blocking strategies did not influence the antineoplastic effects of doxorubicin (a prototypic anthracycline) against MCA205 fibrosarcomas growing in C57BL/6 mice, F244 sarcomas developing in 129/Sv hosts and H2N100 mammary carcinomas arising in BALB/c mice. These findings imply that, in contrast to other cytokines (such as interleukin-1β, interleukin-17 and interferon γ), TNFα is not required for anthracyclines to elicit therapeutic anticancer immune responses.

Published
2013

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