135 results on '"Rodriguez PC"'
Search Results
2. Continuous rearrangement of the postsynaptic gephyrin scaffolding domain: a super-resolution quantified and energetic approach
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Rodriguez Pc, Antoine Triller, and Almeida Lg
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Scaffold protein ,0303 health sciences ,Gephyrin ,biology ,Chemistry ,Plasticity ,03 medical and health sciences ,0302 clinical medicine ,Postsynaptic potential ,Biophysics ,biology.protein ,Photoactivated localization microscopy ,Cytoskeleton ,Postsynaptic density ,030217 neurology & neurosurgery ,Presynaptic active zone ,030304 developmental biology - Abstract
Synaptic function and plasticity requires a delicate balance between overall structural stability and the continuous rearrangement of the components that make up the presynaptic active zone and the postsynaptic density (PSD). Photoactivated localization microscopy (PALM) has provided a detailed view of the nanoscopic structure and organization of some of these synaptic elements. Still lacking, are tools to address the morphing and stability of such complexes at super-resolution. We describe an approach to quantify morphological changes and energetic states of multimolecular assemblies over time. With this method, we studied the scaffold protein gephyrin, which forms postsynaptic clusters that play a key role in the stabilization of receptors at inhibitory synapses. Postsynaptic gephyrin clusters exhibit an internal microstructure composed of nanodomains. We found, that within the PSD, gephyrin molecules continuously undergo spatial reorganization. This dynamic behavior depends on neuronal activity and cytoskeleton integrity. The proposed approach also allowed access to the effective energy responsible for the tenacity of the PSD despite molecular instability.Significant statementSuper-resolution microscopy has become an important tool for the study of biological systems, allowing detailed, nano-scale structural reconstruction, single molecule tracking, particle counting, and interaction studies. However, quantification tools that take full advantage of the information provided by this technology are still lacking. We describe a novel quantification method to obtain information related to the size, directionality, dynamics, and stability of clustered structures from super-resolution microscopy. With this method, we studied the stability of gephyrin clusters, the main inhibitory scaffold protein. We found that gephyrin molecules continuously undergo reorganization based on neuronal activity and changes in the cytoskeleton.
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- 2017
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3. Participation of phosphofructokinase, malate dehydrogenase and isocitrate dehydrogenase in capacitation and acrosome reaction of boar spermatozoa
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Breininger, E, primary, Dubois, D, additional, Pereyra, VE, additional, Rodriguez, PC, additional, Satorre, MM, additional, and Cetica, PD, additional
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- 2017
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4. Nitric Oxide and Superoxide Anion Production During Heparin‐Induced Capacitation in Cryopreserved Bovine Spermatozoa
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Rodriguez, PC, primary, Valdez, LB, additional, Zaobornyj, T, additional, Boveris, A, additional, and Beconi, MT, additional
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- 2011
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5. A pan-cancer gamma delta T cell repertoire.
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Yu X, Song L, Cen L, Cao B, Tao R, Shen Y, Abate-Daga D, Rodriguez PC, Conejo-Garcia JR, and Wang X
- Abstract
This report presents the largest collection of gamma-delta T cell receptor (γδ TCR) reads in human cancer to date, analyzing about 11,000 patient tumor samples across 33 cancer types using the TRUST4 algorithm. Despite γδ T cells being a small fraction of the T cell population, they play a key role in both innate and adaptive immunity. Our comprehensive analysis reveals their significant presence across all cancer types, specifically highlighting the diverse spectrum and clonality patterns of their γδ receptors. This research highlights the complex roles of γδ T cells in tumor tissues and their potential as prognostic biomarkers. We also demonstrate the utility of T cell receptor gamma (TRG) and delta (TRD) gene expression values from standard RNA-seq data. Ultimately, our work establishes a fundamental resource for future tumor-infiltrating γδ T cell research and may facilitate the development of novel γδ-T-cell-based therapeutic strategies. Together, we demonstrate the strong diversity and prognostic potential of γδ T cells in multiple cancer types.
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- 2024
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6. Multicellular immune ecotypes within solid tumors predict real-world therapeutic benefits with immune checkpoint inhibitors.
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Wang X, Li T, Eljilany I, Sukrithan V, Ratan A, McCarter M, Carpten J, Colman H, Ikeguchi AP, Puzanov I, Arnold S, Churchman M, Hwu P, Rodriguez PC, Dalton WS, Weiner GJ, and Tarhini AA
- Abstract
Background: Cancer initiation, progression, and immune evasion depend on the tumor microenvironment (TME). Thus, understanding the TME immune architecture is essential for understanding tumor metastasis and therapy response. This study aimed to create an immune cell states (CSs) atlas using bulk RNA-seq data enriched by eco-type analyses to resolve the complex immune architectures in the TME., Methods: We employed EcoTyper, a machine-learning (ML) framework, to study the real-world prognostic significance of immune CSs and multicellular ecosystems, utilizing molecular data from 1,610 patients with multiple malignancies who underwent immune checkpoint inhibitor (ICI) therapy within the ORIEN Avatar cohort, a well-annotated real-world dataset., Results: Our analysis revealed consistent ICI-specific prognostic TME carcinoma ecotypes (CEs) (including CE1, CE9, CE10) across our pan-cancer dataset, where CE1 being more lymphocyte-deficient and CE10 being more proinflammatory. Also, the analysis of specific immune CSs across different cancers showed consistent CD8+ and CD4+ T cell CS distribution patterns. Furthermore, survival analysis of the ORIEN ICI cohort demonstrated that ecotype CE9 is associated with the most favorable survival outcomes, while CE2 is linked to the least favorable outcomes. Notably, the melanoma-specific prognostic EcoTyper model confirmed that lower predicted risk scores are associated with improved survival and better response to immunotherapy. Finally, de novo discovery of ecotypes in the ORIEN ICI dataset identified Ecotype E3 as significantly associated with poorer survival outcomes., Conclusion: Our findings offer important insights into refining the patient selection process for immunotherapy in real-world practice and guiding the creation of novel therapeutic strategies to target specific ecotypes within the TME., Competing Interests: Conflicts of Interest: IE, MLC, JC, API, WSD, GJW, and PH declare no conflicts of interest. VS declares receiving research funding from Eli Lilly and Company and Crinetics Pharmaceuticals. Consulting for GE Health. Advisory Board member of Exelixis. Receiving speaking fees from Lantheus Pharmaceuticals. MM declares contracted research grants with Merck, Taiho, and the National Comprehensive Cancer Network. IP declares Program Leader (1.2 cal months) for NIH/NCI Cancer Center Support Grant (P30CA016056); consulting with Nouscom, Iovance, Nektar, and Regeneron; stock owner with Ideaya, Inc. HC declares advisory board/consultant: Best Doctors/Teladoc, Orbus Therapeutics, Bristol Meyers Squibb, Regeneron, Novocure, and PPD/Chimerix; research funding (site PI/institutional contract): Orbus, GCAR, Array BioPharma, Karyopharm Therapeutics, Nuvation Bio, Bayer, Bristol Meyer Squib, and Sumitomo Dainippon Pharma. To date, S.M.A. is a member of ASCO COI. A.A.T.declares contracted research grants with institution from Bristol Myers Squib, Genentech-Roche, Regeneron, Sanofi-Genzyme, Nektar, Clinigen, Merck, Acrotech, Pfizer, Checkmate, OncoSec, Scholar Rock, InflaRx GmbH, Agenus; personal consultant/advisory board fees from Bristol Myers Squibb, Merck, Easai, Instil Bio, Clinigin, Regeneron, Sanofi-Genzyme, Novartis, Partner Therapeutics, Genentech/Roche, BioNTech, Concert AI, AstraZeneca outside the submitted work.
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- 2024
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7. Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.
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Mandula JK, Sierra-Mondragon RA, Jimenez RV, Chang D, Mohamed E, Chang S, Vazquez-Martinez JA, Cao Y, Anadon CM, Lee SB, Das S, Rocha-Munguba L, Pham VM, Li R, Tarhini AA, Furqan M, Dalton W, Churchman M, Moran-Segura CM, Nguyen J, Perez B, Kojetin DJ, Obermayer A, Yu X, Chen A, Shaw TI, Conejo-Garcia JR, and Rodriguez PC
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- Animals, Humans, Mice, Calcium-Binding Proteins metabolism, Calcium-Binding Proteins genetics, Cell Line, Tumor, Jagged-1 Protein metabolism, Jagged-1 Protein genetics, Macrophages immunology, Macrophages metabolism, Mice, Inbred C57BL, Receptor, Notch1 metabolism, Receptor, Notch1 genetics, Receptors, Notch metabolism, Signal Transduction, Tumor Escape immunology, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung metabolism, Interferon Regulatory Factors metabolism, Interferon Regulatory Factors genetics, Jagged-2 Protein metabolism, Jagged-2 Protein genetics, Jagged-2 Protein immunology, Lung Neoplasms immunology, Lung Neoplasms pathology, Lung Neoplasms genetics, Mice, Knockout, Tumor-Associated Macrophages immunology, Tumor-Associated Macrophages metabolism
- Abstract
Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2
-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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8. Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.
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De Leo A, Ugolini A, Yu X, Scirocchi F, Scocozza D, Peixoto B, Pace A, D'Angelo L, Liu JKC, Etame AB, Rughetti A, Nuti M, Santoro A, Vogelbaum MA, Conejo-Garcia JR, Rodriguez PC, and Veglia F
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- Animals, Mice, Humans, Cell Line, Tumor, Brain Neoplasms immunology, Brain Neoplasms metabolism, Brain Neoplasms pathology, Glucose Transporter Type 1 metabolism, Glucose Transporter Type 1 genetics, Interleukin-10 metabolism, Glycolysis, Microglia metabolism, Microglia immunology, Mice, Inbred C57BL, T-Lymphocytes immunology, T-Lymphocytes metabolism, Immune Tolerance, Glioblastoma immunology, Glioblastoma metabolism, Glioblastoma pathology, Histones metabolism, Macrophages immunology, Macrophages metabolism, Glucose metabolism
- Abstract
Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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9. Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma.
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Faramand RG, Lee SB, Jain MD, Cao B, Wang X, Rejeski K, Subklewe M, Fahrmann JF, Saini NY, Hanash SM, Kang YP, Chang D, Rodriguez PC, Dean EA, Nishihori T, Shah BD, Lazaryan A, Chavez J, Khimani F, Pinilla-Ibarz JA, Dam M, Reid KM, Corallo SA, Menges M, Hidalgo Vargas M, Mandula JK, Holliday BA, Bachmeier CA, Speth K, Song Q, Mattie M, Locke FL, and Davila ML
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- Humans, Adaptor Proteins, Signal Transducing, Antigens, CD19 therapeutic use, Blood Proteins, C-Reactive Protein, Ferritins, Receptors, Chimeric Antigen therapeutic use, Lymphoma, Large B-Cell, Diffuse therapy, Hematologic Neoplasms
- Abstract
A subset of patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 chimeric antigen receptor (CAR) T-cell therapy have poor clinical outcomes. We report serum proteins associated with severe immune-mediated toxicities and inferior clinical responses in 146 patients with DLBCL treated with axicabtagene ciloleucel. We develop a simple stratification based on pre-lymphodepletion C reactive protein (CRP) and ferritin to classify patients into low-, intermediate-, and high-risk groups. We observe that patients in the high-risk category were more likely to develop grade ≥3 toxicities and had inferior overall and progression-free survival. We sought to validate our findings with two independent international cohorts demonstrating that patients classified as low-risk have excellent efficacy and safety outcomes. Based on routine and readily available laboratory tests that can be obtained prior to lymphodepleting chemotherapy, this simple risk stratification can inform patient selection for CAR T-cell therapy., Significance: CAR T-cell therapy has changed the treatment paradigm for patients with relapsed/refractory hematologic malignancies. Despite encouraging efficacy, a subset of patients have poor clinical outcomes. We show that a simple clinically applicable model using pre-lymphodepletion CRP and ferritin can identify patients at high risk of poor outcomes. This article is featured in Selected Articles from This Issue, p. 80., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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10. Introduction to the special issue: B cells in cancer immunosurveillance.
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Conejo-Garcia JR and Rodriguez PC
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- Humans, Monitoring, Immunologic, Killer Cells, Natural, B-Lymphocytes, Neoplasms therapy
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- 2024
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11. Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.
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Hwang SM, Awasthi D, Jeong J, Sandoval TA, Chae CS, Ramos Y, Tan C, Falco MM, McBain IT, Mishra B, Ivashkiv LB, Zamarin D, Cantillo E, Chapman-Davis E, Holcomb K, Morales DK, Rodriguez PC, Conejo-Garcia JR, Kaczocha M, Vähärautio A, Song M, and Cubillos-Ruiz JR
- Abstract
Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids
1-3 . During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8+ T cells4,5 . Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal CD8+ T cell fatty acid uptake, mitochondrial respiration, and anti-cancer function. We found that TAGLN2 interacts with FABP5, enabling the surface localization of this lipid importer on activated CD8+ T cells. Analysis of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses elicited by the tumor microenvironment repress TAGLN2 in infiltrating CD8+ T cells, enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells bolstered their lipid uptake, mitochondrial respiration, and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumor-induced ER stress and demonstrated superior therapeutic efficacy in mice with metastatic ovarian cancer. Our study unveils the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis., Competing Interests: COMPETING INTERESTS / DISCLOSURES J.R.C.-R. holds patents on the use immune modulators for OvCa treatment and serves as scientific consultant for Moderna, Immagene B.V., and Autoimmunity Biologic Solutions, Inc. D.Z. reports institutional grants from Merck, Genentech, AstraZeneca, Plexxikon, and Synthekine, and personal fees from AstraZeneca, Xencor, Memgen, Takeda, Synthekine, Immunos, Tessa Therapeutics, Miltenyi, and Calidi Biotherapeutics. D.Z. owns a patent on use of oncolytic Newcastle Disease Virus for cancer therapy. J.R.C.-G. has stock options in Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics; receives licensing fees from Anixa Biosciences for the patent of FSHCER T cells; receives honorarium from Alloy Therapeutics; and intellectual property with Compass Therapeutics and Anixa Biosciences; and is co-founder of Cellepus Therapeutics, a company that develops allogeneic gamma/delta CAR T cells. All other authors declare no potential conflicts of interest.- Published
- 2023
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12. Differential requirements for CD4+ T cells in the efficacy of the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank and brain metastasis models.
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Phadke MS, Li J, Chen Z, Rodriguez PC, Mandula JK, Karapetyan L, Forsyth PA, Chen YA, and Smalley KSM
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- Animals, Humans, CD4-Positive T-Lymphocytes, CTLA-4 Antigen, T-Lymphocytes, Cytotoxic metabolism, Brain Neoplasms drug therapy, Brain Neoplasms metabolism, Melanoma, Experimental
- Abstract
Background: Although the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combinations are effective in advanced melanoma, it remains unclear whether their mechanisms of action overlap., Methods: We used single cell (sc) RNA-seq, flow cytometry and IHC analysis of responding SM1, D4M-UV2 and B16 melanoma flank tumors and SM1 brain metastases to explore the mechanism of action of the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combination. CD4+ and CD8+ T cell depletion, tetramer binding assays and ELISPOT assays were used to demonstrate the unique role of CD4+T cell help in the antitumor effects of the anti-PD-1+LAG-3 combination., Results: The anti-PD-1+CTLA-4 combination was associated with the infiltration of FOXP3+regulatory CD4+ cells (Tregs), fewer activated CD4+T cells and the accumulation of a subset of IFNγ secreting cytotoxic CD8+T cells, whereas the anti-PD-1+LAG-3 combination led to the accumulation of CD4+T helper cells that expressed CXCR4, TNFSF8, IL21R and a subset of CD8+T cells with reduced expression of cytotoxic markers. T cell depletion studies showed a requirement for CD4+T cells for the anti-PD-1+LAG-3 combination, but not the PD-1-CTLA-4 combination at both flank and brain tumor sites. In anti-PD-1+LAG-3 treated tumors, CD4+T cell depletion was associated with fewer activated (CD69+) CD8+T cells and impaired IFNγ release but, conversely, increased numbers of activated CD8+T cells and IFNγ release in anti-PD-1+CTLA-4 treated tumors., Conclusions: Together these studies suggest that these two clinically relevant immune checkpoint inhibitor (ICI) combinations have differential effects on CD4+T cell polarization, which in turn, impacted cytotoxic CD8+T cell function. Further insights into the mechanisms of action/resistance of these clinically-relevant ICI combinations will allow therapy to be further personalized., Competing Interests: Competing interests: KS reports research funding from Revolution Medicines, unrelated to the current study. PF serves as a Consultant to Abbvie, Pfizer, Novartis, BMS, BTG, GSK, Ziopharm, Tocagen, Boehringer Ingelheim, National Brain Tumor Society, Midatech Pharma, Inovio, NCCN unrelated to the current study. All other authors report no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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13. Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers.
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Biswas S, Mandal G, Anadon CM, Chaurio RA, Lopez-Bailon LU, Nagy MZ, Mine JA, Hänggi K, Sprenger KB, Innamarato P, Harro CM, Powers JJ, Johnson J, Fang B, Eysha M, Nan X, Li R, Perez BA, Curiel TJ, Yu X, Rodriguez PC, and Conejo-Garcia JR
- Subjects
- Humans, CD8-Positive T-Lymphocytes metabolism, Proto-Oncogene Proteins p21(ras) metabolism, Cytoplasm metabolism, Immunoglobulin A metabolism, Carcinoma
- Abstract
Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRAS
G12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D -specific dIgA1 limited the growth of KRASG12D -mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers., Competing Interests: Declaration of interests J.R.C.-G. has stock options in Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics; has sponsored research with Anixa Biosciences; receives honorarium from Alloy Therapeutics; and has intellectual property with Compass Therapeutics and Anixa Biosciences; all outside the submitted work. J.R.C.-G. and S.B. have filed a patent application for intracellular targeting of oncodrivers using dIgA. B.A.P. has completed Advisory Board with AstraZeneca and has Research Support from BMS. R.L.: clinical trial protocol committee—CG Oncology; Scientific adviser/consultant—BMS, Ferring, Fergene, Arquer Diagnostics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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14. Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer.
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Eisa NH, Crowley VM, Elahi A, Kommalapati VK, Serwetnyk MA, Llbiyi T, Lu S, Kainth K, Jilani Y, Marasco D, El Andaloussi A, Lee S, Tsai FTF, Rodriguez PC, Munn D, Celis E, Korkaya H, Debbab A, Blagg B, and Chadli A
- Abstract
Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8
+ T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action., Competing Interests: A.C. and Augusta University have a patent (US 11,446,352 B2) related to this work. All other authors have no conflict of interest to declare for this research., (© 2023 The Authors.)- Published
- 2023
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15. Relationships among Inflammatory Biomarkers and Self-Reported Treatment-Related Symptoms in Patients Treated with Chemotherapy for Gynecologic Cancer: A Controlled Comparison.
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Hoogland AI, Small BJ, Oswald LB, Bryant C, Rodriguez Y, Gonzalez BD, Li X, Janelsins MC, Bulls HW, James BW, Arboleda B, Colon-Echevarria C, Townsend MK, Tworoger SS, Rodriguez PC, Bower JE, Apte SM, Wenham RM, and Jim HSL
- Abstract
Previous research suggests that inflammation triggers cancer-treatment-related symptoms (i.e., fatigue, depression, and disruptions in sleep and physical activity), but evidence is mixed. This study examined relationships between inflammatory biomarkers and symptoms in patients with gynecologic cancer compared to age-matched women with no cancer history (i.e., controls). Patients ( n = 121) completed assessments before chemotherapy cycles 1, 3, and 6, and 6 and 12 months later. Controls ( n = 105) completed assessments at similar timepoints. Changes in inflammation and symptomatology were evaluated using random-effects mixed models, and cross-sectional differences between patients and controls in inflammatory biomarkers and symptoms were evaluated using least squares means. Associations among inflammatory biomarkers and symptoms were evaluated using random-effects fluctuation mixed models. The results indicated that compared to controls, patients typically have higher inflammatory biomarkers (i.e., TNF-alpha, TNFR1, TNFR2, CRP, IL-1ra) and worse fatigue, depression, and sleep ( p s < 0.05). Patients reported lower levels of baseline physical activity ( p = 0.02) that became more similar to controls over time. Significant associations were observed between CRP, depression, and physical activity ( p s < 0.05), but not between inflammation and other symptoms. The results suggest that inflammation may not play a significant role in fatigue or sleep disturbance among gynecologic cancer patients but may contribute to depression and physical inactivity.
- Published
- 2023
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16. PATH-SURVEYOR: pathway level survival enquiry for immuno-oncology and drug repurposing.
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Obermayer AN, Chang D, Nobles G, Teng M, Tan AC, Wang X, Chen YA, Eschrich S, Rodriguez PC, Grass GD, Meshinchi S, Tarhini A, Chen DT, and Shaw TI
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- Child, Humans, Drug Repositioning, Medical Oncology, Algorithms, Melanoma drug therapy, Melanoma genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, PATH-SURVEYOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions., (© 2023. The Author(s).)
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- 2023
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17. Affinity-matured DLL4 ligands as broad-spectrum modulators of Notch signaling.
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Gonzalez-Perez D, Das S, Antfolk D, Ahsan HS, Medina E, Dundes CE, Jokhai RT, Egan ED, Blacklow SC, Loh KM, Rodriguez PC, and Luca VC
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- Humans, Animals, Mice, Ligands, Calcium-Binding Proteins metabolism, Signal Transduction physiology, Receptors, Notch metabolism, Adaptor Proteins, Signal Transducing metabolism, Intercellular Signaling Peptides and Proteins metabolism
- Abstract
The Notch pathway regulates cell fate decisions and is an emerging target for regenerative and cancer therapies. Recombinant Notch ligands are attractive candidates for modulating Notch signaling; however, their intrinsically low receptor-binding affinity restricts their utility in biomedical applications. To overcome this limitation, we evolved variants of the ligand Delta-like 4 with enhanced affinity and cross-reactivity. A consensus variant with maximized binding affinity, Delta
MAX , binds human and murine Notch receptors with 500- to 1,000-fold increased affinity compared with wild-type human Delta-like 4. DeltaMAX also potently activates Notch in plate-bound, bead-bound and cellular formats. When administered as a soluble decoy, DeltaMAX inhibits Notch in reporter and neuronal differentiation assays, highlighting its dual utility as an agonist or antagonist. Finally, we demonstrate that DeltaMAX stimulates increased proliferation and expression of effector mediators in T cells. Taken together, our data define DeltaMAX as a versatile tool for broad-spectrum activation or inhibition of Notch signaling., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2023
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18. Neglected no more: B cell-mediated anti-tumor immunity.
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Conejo-Garcia JR, Biswas S, Chaurio R, and Rodriguez PC
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- Animals, Humans, Mice, Adaptive Immunity immunology, B-Lymphocytes immunology, Neoplasms immunology, Neoplasms therapy, T-Lymphocytes immunology, Tertiary Lymphoid Structures immunology
- Abstract
Immuno-oncology has traditionally focused on the cellular arm of the adaptive immune response, while attributing tumor-promoting activity to humoral responses in tumor-bearing hosts. This view stems from mouse models that do not necessarily recapitulate the antibody response process consistently observed in most human cancers. In recent years, the field has reconsidered the coordinated action of T and B cell responses in the context of anti-tumor immunity, as in any other immune response. Thus, recent studies in human cancer identify B cell responses with better outcome, typically in association with superior T cell responses. An area of particular interest is tertiary lymphoid structures, where germinal centers produce isotype switched antibodies and B cells and T lymphocytes interact with other immune cell types. The presence of these lymphoid structures is associated with better immunotherapeutic responses and remain poorly understood. Here, we discuss recent discoveries on how coordination between humoral and cellular responses is required for effective immune pressure against malignant progression, providing a perspective on the role of tertiary lymphoid structures and interventions to elicit their formation in unresectable tumors., (Copyright © 2022. Published by Elsevier Ltd.)
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- 2023
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19. Mineral Soils Are an Important Intermediate Storage Pool of Black Carbon in Fennoscandian Boreal Forests.
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Eckdahl JA, Rodriguez PC, Kristensen JA, Metcalfe DB, and Ljung K
- Abstract
Approximately 40% of earth's carbon (C) stored in land vegetation and soil is within the boreal region. This large C pool is subjected to substantial removals and transformations during periodic wildfire. Fire-altered C, commonly known as pyrogenic carbon (PyC), plays a significant role in forest ecosystem functioning and composes a considerable fraction of C transport to limnic and oceanic sediments. While PyC stores are beginning to be quantified globally, knowledge is lacking regarding the drivers of their production and transport across ecosystems. This study used the chemo-thermal oxidation at 375°C (CTO-375) method to isolate a particularly refractory subset of PyC compounds, here called black carbon (BC), finding an average increase of 11.6 g BC m
-2 at 1 year postfire in 50 separate wildfires occurring in Sweden during 2018. These increases could not be linked to proposed drivers, however BC storage in 50 additional nearby unburnt soils related strongly to soil mass while its proportion of the larger C pool related negatively to soil C:N. Fire approximately doubled BC stocks in the mineral layer but had no significant effect on BC in the organic layer where it was likely produced. Suppressed decomposition rates and low heating during fire in mineral subsoil relative to upper layers suggests potential removals of the doubled mineral layer BC are more likely transported out of the soil system than degraded in situ. Therefore, mineral soils are suggested to be an important storage pool for BC that can buffer short-term (production in fire) and long-term (cross-ecosystem transport) BC cycling., (© 2022. The Authors.)- Published
- 2022
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20. Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity.
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Salvagno C, Mandula JK, Rodriguez PC, and Cubillos-Ruiz JR
- Subjects
- Humans, Endoribonucleases metabolism, Protein Serine-Threonine Kinases, Inositol, Tumor Microenvironment, Endoplasmic Reticulum Stress, Neoplasms pathology
- Abstract
The tumor microenvironment (TME) provokes endoplasmic reticulum (ER) stress in malignant cells and infiltrating immune populations. Sensing and responding to ER stress is coordinated by the unfolded protein response (UPR), an integrated signaling pathway governed by three ER stress sensors: activating transcription factor (ATF6), inositol-requiring enzyme 1α (IRE1α), and protein kinase R (PKR)-like ER kinase (PERK). Persistent UPR activation modulates malignant progression, tumor growth, metastasis, and protective antitumor immunity. Hence, therapies targeting ER stress signaling can be harnessed to elicit direct tumor killing and concomitant anticancer immunity. We highlight recent findings on the role of the ER stress responses in onco-immunology, with an emphasis on genetic vulnerabilities that render tumors highly sensitive to therapeutic UPR modulation., Competing Interests: Declaration of interests J.R.C-R. is a scientific consultant for NextRNA Therapeutics, Inc. and Autoimmunity Biologic Solutions, Inc. P.R. and J.R.C-R. hold patents on targeting ER stress pathways for the treatment of disease. The other authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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21. Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.
- Author
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Mandula JK, Chang S, Mohamed E, Jimenez R, Sierra-Mondragon RA, Chang DC, Obermayer AN, Moran-Segura CM, Das S, Vazquez-Martinez JA, Prieto K, Chen A, Smalley KSM, Czerniecki B, Forsyth P, Koya RC, Ruffell B, Cubillos-Ruiz JR, Munn DH, Shaw TI, Conejo-Garcia JR, and Rodriguez PC
- Subjects
- Animals, Endoplasmic Reticulum Stress, Mice, Signal Transduction, T-Lymphocytes metabolism, Unfolded Protein Response, eIF-2 Kinase genetics, eIF-2 Kinase metabolism, Interferon Type I metabolism, Neoplasms
- Abstract
Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61β-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C
+ CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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22. TCR-Independent Metabolic Reprogramming Precedes Lymphoma-Driven Changes in T-cell Fate.
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Hesterberg RS, Liu M, Elmarsafawi AG, Koomen JM, Welsh EA, Hesterberg SG, Ranatunga S, Yang C, Li W, Lawrence HR, Rodriguez PC, Berglund AE, and Cleveland JL
- Subjects
- Animals, CD4-Positive T-Lymphocytes, Cell Differentiation, Glucose metabolism, Mice, Mice, Transgenic, Receptors, Antigen, T-Cell metabolism, Tumor Microenvironment, Lymphoma metabolism, Lymphoma, B-Cell metabolism
- Abstract
Chronic T-cell receptor (TCR) signaling in the tumor microenvironment is known to promote T-cell dysfunction. However, we reasoned that poorly immunogenic tumors may also compromise T cells by impairing their metabolism. To address this, we assessed temporal changes in T-cell metabolism, fate, and function in models of B-cell lymphoma driven by Myc, a promoter of energetics and repressor of immunogenicity. Increases in lymphoma burden most significantly impaired CD4+ T-cell function and promoted regulatory T cell (Treg) and Th1-cell differentiation. Metabolomic analyses revealed early reprogramming of CD4+ T-cell metabolism, reduced glucose uptake, and impaired mitochondrial function, which preceded changes in T-cell fate. In contrast, B-cell lymphoma metabolism remained robust during tumor progression. Finally, mitochondrial functions were impaired in CD4+ and CD8+ T cells in lymphoma-transplanted OT-II and OT-I transgenic mice, respectively. These findings support a model, whereby early, TCR-independent, metabolic interactions with developing lymphomas limits T cell-mediated immune surveillance., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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23. Tumor-directed dysregulation of erythroid progenitors drives immunosuppressive myeloid cells.
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Mandula JK and Rodriguez PC
- Subjects
- Humans, Immune Tolerance, Immunosuppression Therapy, Myeloid Cells, Myeloid-Derived Suppressor Cells, Neoplasms pathology
- Abstract
In this issue of Cancer Cell, Long et al. demonstrate that tumors can reprogram erythroid progenitors into myeloid-erythroid cells that promote immunosuppression. Erythroid-differentiated myeloid cells (EDMCs) expand in cancer-bearing individuals, resemble the functionality of myeloid-derived suppressor cells (MDSCs), and correlate with poor response to immune-checkpoint inhibitors (ICIs) and tumor-related anemia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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24. Carbon Monoxide Activates PERK-Regulated Autophagy to Induce Immunometabolic Reprogramming and Boost Antitumor T-cell Function.
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Chakraborty P, Parikh RY, Choi S, Tran D, Gooz M, Hedley ZT, Kim DS, Pytel D, Kang I, Nadig SN, Beeson GC, Ball L, Mehrotra M, Wang H, Berto S, Palanisamy V, Li H, Chatterjee S, Rodriguez PC, Maldonado EN, Diehl JA, Gangaraju VK, and Mehrotra S
- Subjects
- Apoptosis, Autophagy, Endoplasmic Reticulum Stress physiology, Humans, T-Lymphocytes metabolism, Carbon Monoxide pharmacology, eIF-2 Kinase genetics, eIF-2 Kinase metabolism
- Abstract
Mitochondria and endoplasmic reticulum (ER) share structural and functional networks and activate well-orchestrated signaling processes to shape cells' fate and function. While persistent ER stress (ERS) response leads to mitochondrial collapse, moderate ERS promotes mitochondrial function. Strategies to boost antitumor T-cell function by targeting ER-mitochondria cross-talk have not yet been exploited. Here, we used carbon monoxide (CO), a short-lived gaseous molecule, to test whether engaging moderate ERS conditions can improve mitochondrial and antitumor functions in T cells. In melanoma antigen-specific T cells, CO-induced transient activation of ERS sensor protein kinase R-like endoplasmic reticulum kinase (PERK) significantly increased antitumor T-cell function. Furthermore, CO-induced PERK activation temporarily halted protein translation and induced protective autophagy, including mitophagy. The use of LC3-GFP enabled differentiation between the cells that prepare themselves to undergo active autophagy (LC3-GFPpos) and those that fail to enter the process (LC3-GFPneg). LC3-GFPpos T cells showed strong antitumor potential, whereas LC3-GFPneg cells exhibited a T regulatory-like phenotype, harbored dysfunctional mitochondria, and accumulated abnormal metabolite content. These anomalous ratios of metabolites rendered the cells with a hypermethylated state and distinct epigenetic profile, limiting their antitumor activity. Overall, this study shows that ERS-activated autophagy pathways modify the mitochondrial function and epigenetically reprogram T cells toward a superior antitumor phenotype to achieve robust tumor control., Significance: Transient activation of ER stress with carbon monoxide drives mitochondrial biogenesis and protective autophagy that elicits superior antitumor T-cell function, revealing an approach to improving adoptive cell efficacy therapy., (©2022 American Association for Cancer Research.)
- Published
- 2022
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25. Single-cell Characterization of the Cellular Landscape of Acral Melanoma Identifies Novel Targets for Immunotherapy.
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Li J, Smalley I, Chen Z, Wu JY, Phadke MS, Teer JK, Nguyen T, Karreth FA, Koomen JM, Sarnaik AA, Zager JS, Khushalani NI, Tarhini AA, Sondak VK, Rodriguez PC, Messina JL, Chen YA, and Smalley KSM
- Subjects
- Humans, Immunologic Factors therapeutic use, Immunotherapy, Skin pathology, Melanoma, Cutaneous Malignant, Melanoma drug therapy, Melanoma therapy, Neoplasms, Second Primary, Skin Neoplasms drug therapy, Skin Neoplasms therapy
- Abstract
Purpose: Acral melanoma is a rare subtype of melanoma that arises on the non-hair-bearing skin of the palms, soles, and nail beds. In this study, we used single-cell RNA sequencing (scRNA-seq) to map the transcriptional landscape of acral melanoma and identify novel immunotherapeutic targets., Experimental Design: We performed scRNA-seq on nine clinical specimens (five primary, four metastases) of acral melanoma. Detailed cell type curation was performed, the immune landscapes were mapped, and key results were validated by analysis of The Cancer Genome Atlas (TCGA) and single-cell datasets. Cell-cell interactions were inferred and compared with those in nonacral cutaneous melanoma., Results: Multiple phenotypic subsets of T cells, natural killer (NK) cells, B cells, macrophages, and dendritic cells with varying levels of activation/exhaustion were identified. A comparison between primary and metastatic acral melanoma identified gene signatures associated with changes in immune responses and metabolism. Acral melanoma was characterized by a lower overall immune infiltrate, fewer effector CD8 T cells and NK cells, and a near-complete absence of γδ T cells compared with nonacral cutaneous melanomas. Immune cells associated with acral melanoma exhibited expression of multiple checkpoints including PD-1, LAG-3, CTLA-4, V-domain immunoglobin suppressor of T cell activation (VISTA), TIGIT, and the Adenosine A2A receptor (ADORA2). VISTA was expressed in 58.3% of myeloid cells and TIGIT was expressed in 22.3% of T/NK cells., Conclusions: Acral melanoma has a suppressed immune environment compared with that of cutaneous melanoma from nonacral skin. Expression of multiple, therapeutically tractable immune checkpoints were observed, offering new options for clinical translation., (©2022 American Association for Cancer Research.)
- Published
- 2022
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26. Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory T cells.
- Author
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Anadon CM, Yu X, Hänggi K, Biswas S, Chaurio RA, Martin A, Payne KK, Mandal G, Innamarato P, Harro CM, Mine JA, Sprenger KB, Cortina C, Powers JJ, Costich TL, Perez BA, Gatenbee CD, Prabhakaran S, Marchion D, Heemskerk MHM, Curiel TJ, Anderson AR, Wenham RM, Rodriguez PC, and Conejo-Garcia JR
- Subjects
- CD8-Positive T-Lymphocytes, Female, Humans, Lymphocytes, Tumor-Infiltrating, Memory T Cells, Immunologic Memory, Ovarian Neoplasms
- Abstract
Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating T cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3
+ CD8+ CD103+ CD69+ TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers shows that only progenitor (TCF1low ) tissue-resident T cells (TRMstem cells), but not recirculating TCF1+ T cells, predict ovarian cancer outcome. TRMstem cells arise from transitional recirculating T cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease, but that depends on ∼13% of CD8+ tumor-infiltrating T cells (∼3% of CD8+ clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM-like cells. Our results define the signature of relevant tumor-reactive T cells in human ovarian cancer, which could be applicable to other tumors with unideal mutational burden., Competing Interests: Declaration of interests J.R.C.-G. has stock options with Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics; receives honorarium from Anixa Biosciences, Alloy Therapeutics, and Leidos; and has sponsored research with Anixa Biosciences (all outside the submitted work). B.A.P. has served on the Advisory Board of AstraZeneca and has research support from BMS. J.R.C.-G. is currently an employee of STEMCELL Technologies (all work outside the submitted work). R.M.W. reports grants and personal fees from Merck, personal fees from Tesaro/GSK, personal fees from Genentech, personal fees from Legend Biotech, personal fees from AbbVie, personal fees from Astrazeneca, grants and stock from Ovation Diagnostics, personal fees from Clovis Oncology, and personal fees from Regeneron (all outside the submitted work)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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27. Agonists of prostaglandin E 2 receptors as potential first in class treatment for nephronophthisis and related ciliopathies.
- Author
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Garcia H, Serafin AS, Silbermann F, Porée E, Viau A, Mahaut C, Billot K, Birgy É, Garfa-Traore M, Roy S, Ceccarelli S, Mehraz M, Rodriguez PC, Deleglise B, Furio L, Jabot-Hanin F, Cagnard N, Del Nery E, Fila M, Sin-Monnot S, Antignac C, Lyonnet S, Krug P, Salomon R, Annereau JP, Benmerah A, Delous M, Briseño-Roa L, and Saunier S
- Subjects
- Animals, Cilia metabolism, Female, Humans, Kidney Diseases, Cystic congenital, Male, Mice, Prostaglandins metabolism, Receptors, Prostaglandin E metabolism, Zebrafish, Ciliopathies drug therapy, Ciliopathies genetics, Ciliopathies metabolism, Polycystic Kidney Diseases metabolism
- Abstract
Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using a medium-throughput drug-screen in NPHP1 knockdown cells, we identified 51 Food and Drug Administration-approved compounds by their ability to alleviate the cellular phenotypes associated with the loss of NPHP1; 11 compounds were further selected for their physicochemical properties. Among those compounds, prostaglandin E1 (PGE1) rescued ciliogenesis defects in immortalized patient NPHP1 urine-derived renal tubular cells, and improved ciliary and kidney phenotypes in our NPH zebrafish and Nphp1 knockout mouse models. Furthermore, Taprenepag, a nonprostanoid prostaglandin E2 receptor agonist, alleviated the severe retinopathy observed in Nphp1−/− mice. Finally, comparative transcriptomics allowed identification of key signaling pathways downstream PGE1, including cell cycle progression, extracellular matrix, adhesion, or actin cytoskeleton organization. In conclusion, using in vitro and in vivo models, we showed that prostaglandin E2 receptor agonists can ameliorate several of the pleotropic phenotypes caused by the absence of NPHP1; this opens their potential as a first therapeutic option for juvenile NPH-associated ciliopathies.
- Published
- 2022
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28. Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma.
- Author
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Song X, Chang S, Seminario-Vidal L, de Mingo Pulido A, Tordesillas L, Song X, Reed RA, Harkins A, Whiddon S, Nguyen JV, Segura CM, Zhang C, Yoder S, Sayegh Z, Zhao Y, Messina JL, Harro CM, Zhang X, Conejo-Garcia JR, Berglund A, Sokol L, Zhang J, Rodriguez PC, Mulé JJ, Futreal AP, Tsai KY, and Chen PL
- Subjects
- Cell Transformation, Neoplastic, Ecosystem, Genomics, Humans, Lymphoma, T-Cell, Cutaneous drug therapy, Lymphoma, T-Cell, Cutaneous genetics, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Skin Neoplasms metabolism
- Abstract
Abstract: Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided in situ evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74., Significance: Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma. This article is highlighted in the In This Issue feature, p. 1171., (©2022 American Association for Cancer Research.)
- Published
- 2022
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29. IgA-Dominated Humoral Immune Responses Govern Patients' Outcome in Endometrial Cancer.
- Author
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Mandal G, Biswas S, Anadon CM, Yu X, Gatenbee CD, Prabhakaran S, Payne KK, Chaurio RA, Martin A, Innamarato P, Moran C, Powers JJ, Harro CM, Mine JA, Sprenger KB, Rigolizzo KE, Wang X, Curiel TJ, Rodriguez PC, Anderson AR, Saglam O, and Conejo-Garcia JR
- Subjects
- B-Lymphocytes metabolism, Female, Humans, Immunity, Humoral, Immunoglobulin A metabolism, Tumor Microenvironment, Endometrial Neoplasms pathology, Receptors, Polymeric Immunoglobulin genetics, Receptors, Polymeric Immunoglobulin metabolism
- Abstract
Recent studies suggest that B cells could play an important role in the tumor microenvironment. However, the role of humoral responses in endometrial cancer remains insufficiently investigated. Using a cohort of 107 patients with different histological subtypes of endometrial carcinoma, we evaluated the role of coordinated humoral and cellular adaptive immune responses in endometrial cancer. Concomitant accumulation of T, B, and plasma cells at tumor beds predicted better survival. However, only B-cell markers corresponded with prolonged survival specifically in high-grade endometrioid type and serous tumors. Immune protection was associated with class-switched IgA and, to a lesser extent, IgG. Expressions of polymeric immunoglobulin receptor (pIgR) by tumor cells and its occupancy by IgA were superior predictors of outcome and correlated with defects in methyl-directed DNA mismatch repair. Mechanistically, pIgR-dependent, antigen-independent IgA occupancy drove activation of inflammatory pathways associated with IFN and TNF signaling in tumor cells, along with apoptotic and endoplasmic reticulum stress pathways, while thwarting DNA repair mechanisms. Together, these findings suggest that coordinated humoral and cellular immune responses, characterized by IgA:pIgR interactions in tumor cells, determine the progression of human endometrial cancer as well as the potential for effective immunotherapies., Significance: This study provides new insights into the crucial role of humoral immunity in human endometrial cancer, providing a rationale for designing novel immunotherapies against this prevalent malignancy. See related commentary by Osorio and Zamarin, p. 766., (©2021 American Association for Cancer Research.)
- Published
- 2022
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30. Increased inflammatory low-density neutrophils in severe obesity and effect of bariatric surgery: Results from case-control and prospective cohort studies.
- Author
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Sanchez-Pino MD, Richardson WS, Zabaleta J, Puttalingaiah RT, Chapple AG, Liu J, Kim Y, Ponder M, DeArmitt R, Baiamonte LB, Wyczechowska D, Zheng L, Al-Khami AA, Garai J, Martini R, Davis M, Gorham JK, Wooldridge JB, Rodriguez PC, Miele L, and Ochoa AC
- Subjects
- Case-Control Studies, Humans, Longitudinal Studies, Neutrophils metabolism, Prospective Studies, Bariatric Surgery methods, Obesity, Morbid complications, Obesity, Morbid metabolism, Obesity, Morbid surgery
- Abstract
Background: Low-density neutrophils (LDN) are increased in several inflammatory diseases and may also play a role in the low-grade chronic inflammation associated with obesity. Here we explored their role in obesity, determined their gene signatures, and assessed the effect of bariatric surgery., Methods: We compared the number, function, and gene expression profiles of circulating LDN in morbidly obese patients (MOP, n=27; body mass index (BMI) > 40 Kg/m
2 ) and normal-weight controls (NWC, n=20; BMI < 25 Kg/m2 ) in a case-control study. Additionally, in a prospective longitudinal study, we measured changes in the frequency of LDN after bariatric surgery (n=36) and tested for associations with metabolic and inflammatory parameters., Findings: LDN and inflammatory markers were significantly increased in MOP compared to NWC. Transcriptome analysis showed increased neutrophil-related gene expression signatures associated with inflammation, neutrophil activation, and immunosuppressive function. However, LDN did not suppress T cells proliferation and produced low levels of reactive oxygen species (ROS). Circulating LDN in MOP significantly decreased after bariatric surgery in parallel with BMI, metabolic syndrome, and inflammatory markers., Interpretation: Obesity increases LDN displaying an inflammatory gene signature. Our results suggest that LDN may represent a neutrophil subset associated with chronic inflammation, a feature of obesity that has been previously associated with the appearance and progression of co-morbidities. Furthermore, bariatric surgery, as an efficient therapy for severe obesity, reduces LDN in circulation and improves several components of the metabolic syndrome supporting its recognized anti-inflammatory and beneficial metabolic effects., Funding: This work was supported in part by grants from the National Institutes of Health (NIH; 5P30GM114732-02, P20CA233374 - A. Ochoa and L. Miele), Pennington Biomedical NORC (P30DK072476 - E. Ravussin & LSU-NO Stanley S. Scott Cancer Center and Louisiana Clinical and Translational Science Center (LACaTS; U54-GM104940 - J. Kirwan)., Competing Interests: Declaration of interests Augusto Ochoa, and Lucio Miele were funded by grants from the National Cancer Institute and the National Institutes of Health. The remaining authors have declared that no conflict of interest exists., (Published by Elsevier B.V.)- Published
- 2022
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31. TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures.
- Author
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Chaurio RA, Anadon CM, Lee Costich T, Payne KK, Biswas S, Harro CM, Moran C, Ortiz AC, Cortina C, Rigolizzo KE, Sprenger KB, Mine JA, Innamarato P, Mandal G, Powers JJ, Martin A, Wang Z, Mehta S, Perez BA, Li R, Robinson J, Kroeger JL, Curiel TJ, Yu X, Rodriguez PC, and Conejo-Garcia JR
- Subjects
- Animals, Cell Differentiation, Gene Expression Regulation, Gene Silencing, Genotype, Matrix Attachment Region Binding Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor metabolism, Transforming Growth Factor beta genetics, Germinal Center immunology, Lymphocytes, Tumor-Infiltrating immunology, Matrix Attachment Region Binding Proteins metabolism, T-Lymphocytes, Helper-Inducer immunology, Tertiary Lymphoid Structures immunology, Transforming Growth Factor beta metabolism
- Abstract
The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4
Cre Satb1f/f mice enriched for antigen-specific Tfh cells, and TGF-β-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1-/- CD4+ T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4Cre Satb1f/f mice accumulated tumor antigen-specific, LIGHT+ CXCL13+ IL-21+ Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4+ T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4+ T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-β-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors., Competing Interests: Declaration of interests J.R.C.-G. has stock options with Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics, receives honorarium from Anixa Biosciences, Alloy Therapeutics, and Leidos, and has sponsored research with Anixa Biosciences. R.L.: Clinical trial protocol committee–CG oncology; Scientific advisor/consultant–B.M.S., Ferring, Fergene, Arquer Diagnostics. B.A.P. has completed Advisory Board with AstraZeneca and has Research Support from B.M.S. J.R. is currently an employee of STEMCELL Technologies., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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32. Identification of Immunogenic MHC Class II Human HER3 Peptides that Mediate Anti-HER3 CD4 + Th1 Responses and Potential Use as a Cancer Vaccine.
- Author
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Basu A, Albert GK, Awshah S, Datta J, Kodumudi KN, Gallen C, Beyer A, Smalley KSM, Rodriguez PC, Duckett DR, Forsyth PA, Soyano A, Koski GK, Lima Barros Costa R, Han H, Soliman H, Lee MC, Kalinski P, and Czerniecki BJ
- Subjects
- Amino Acid Sequence, Animals, Breast Neoplasms immunology, Breast Neoplasms metabolism, Cell Line, Tumor, Dendritic Cells immunology, Epitopes, T-Lymphocyte immunology, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Survival Analysis, Th1 Cells immunology, Treatment Outcome, Tumor Burden drug effects, Tumor Burden immunology, Breast Neoplasms therapy, CD4-Positive T-Lymphocytes immunology, Cancer Vaccines immunology, Histocompatibility Antigens Class II metabolism, Receptor, ErbB-3 metabolism
- Abstract
The HER3/ERBB3 receptor is an oncogenic receptor tyrosine kinase that forms heterodimers with EGFR family members and is overexpressed in numerous cancers. HER3 overexpression associates with reduced survival and acquired resistance to targeted therapies, making it a potential therapeutic target in multiple cancer types. Here, we report on immunogenic, promiscuous MHC class II-binding HER3 peptides, which can generate HER3-specific CD4
+ Th1 antitumor immune responses. Using an overlapping peptide screening methodology, we identified nine MHC class II-binding HER3 epitopes that elicited specific Th1 immune response in both healthy donors and breast cancer patients. Most of these peptides were not identified by current binding algorithms. Homology assessment of amino acid sequence BLAST showed >90% sequence similarity between human and murine HER3/ERBB3 peptide sequences. HER3 peptide-pulsed dendritic cell vaccination resulted in anti-HER3 CD4+ Th1 responses that prevented tumor development, significantly delayed tumor growth in prevention models, and caused regression in multiple therapeutic models of HER3-expressing murine tumors, including mammary carcinoma and melanoma. Tumors were robustly infiltrated with CD4+ T cells, suggesting their key role in tumor rejection. Our data demonstrate that class II HER3 promiscuous peptides are effective at inducing HER3-specific CD4+ Th1 responses and suggest their applicability in immunotherapies for human HER3-overexpressing tumors., (©2021 The Authors; Published by the American Association for Cancer Research.)- Published
- 2022
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33. Single-Cell Characterization of the Immune Microenvironment of Melanoma Brain and Leptomeningeal Metastases.
- Author
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Smalley I, Chen Z, Phadke M, Li J, Yu X, Wyatt C, Evernden B, Messina JL, Sarnaik A, Sondak VK, Zhang C, Law V, Tran N, Etame A, Macaulay RJB, Eroglu Z, Forsyth PA, Rodriguez PC, Chen YA, and Smalley KSM
- Subjects
- Humans, Brain Neoplasms immunology, Brain Neoplasms secondary, Melanoma immunology, Melanoma pathology, Melanoma secondary, Meningeal Neoplasms immunology, Meningeal Neoplasms secondary, Skin Neoplasms immunology, Skin Neoplasms pathology, Tumor Microenvironment immunology
- Abstract
Purpose: Melanoma brain metastases (MBM) and leptomeningeal melanoma metastases (LMM) are two different manifestations of melanoma CNS metastasis. Here, we used single-cell RNA sequencing (scRNA-seq) to define the immune landscape of MBM, LMM, and melanoma skin metastases., Experimental Design: scRNA-seq was undertaken on 43 patient specimens, including 8 skin metastases, 14 MBM, and 19 serial LMM specimens. Detailed cell type curation was performed, the immune landscapes were mapped, and key results were validated by IHC and flow cytometry. Association analyses were undertaken to identify immune cell subsets correlated with overall survival., Results: The LMM microenvironment was characterized by an immune-suppressed T-cell landscape distinct from that of brain and skin metastases. An LMM patient with long-term survival demonstrated an immune repertoire distinct from that of poor survivors and more similar to normal cerebrospinal fluid (CSF). Upon response to PD-1 therapy, this extreme responder showed increased levels of T cells and dendritic cells in their CSF, whereas poor survivors showed little improvement in their T-cell responses. In MBM patients, therapy led to increased immune infiltrate, with similar T-cell transcriptional diversity noted between skin metastases and MBM. A correlation analysis across the entire immune landscape identified the presence of a rare population of dendritic cells (DC3) that was associated with increased overall survival and positively regulated the immune environment through modulation of activated T cells and MHC expression., Conclusions: Our study provides the first atlas of two distinct sites of melanoma CNS metastases and defines the immune cell landscape that underlies the biology of this devastating disease., (©2021 American Association for Cancer Research.)
- Published
- 2021
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34. Cavity macrophages stop anti-tumor T cells.
- Author
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Rodriguez PC and Ruffell B
- Subjects
- Immunotherapy, Macrophages, T-Lymphocytes, Cytotoxic, Hepatitis A Virus Cellular Receptor 2, T-Lymphocytes, Regulatory
- Abstract
Precisely how macrophages regulate response to immunotherapy remains unclear. In this issue of Cancer Cell, Chow et al. demonstrate a tumor-promoting role of TIM-4
+ cavity macrophages which affects the response of metastatic malignancies to immunotherapy. Specifically, TIM-4+ macrophages engage with phosphatidylserine-expressing cytotoxic T lymphocytes, inhibiting their activity even during PD-1 blockade., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
35. Innate immune cells in the tumor microenvironment.
- Author
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Li MO, Wolf N, Raulet DH, Akkari L, Pittet MJ, Rodriguez PC, Kaplan RN, Munitz A, Zhang Z, Cheng S, and Bhardwaj N
- Subjects
- Cancer Vaccines pharmacology, Dendritic Cells immunology, Humans, Killer Cells, Natural immunology, Lymphocytes pathology, Mast Cells immunology, Mast Cells pathology, Myeloid-Derived Suppressor Cells immunology, Neoplasms immunology, Neoplasms pathology, Neutrophils immunology, Tumor-Associated Macrophages immunology, Tumor-Associated Macrophages pathology, Immunity, Innate, Immunotherapy methods, Lymphocytes immunology, Neoplasms therapy, Tumor Microenvironment immunology
- Abstract
The tumor immune microenvironment (TIME) is a complex ecosystem that contains adaptive and innate immune cells that have tumor-promoting and anti-tumor effects. There is still much to learn about the diversity, plasticity, and functions of innate immune cells in the TIME and their roles in determining the response to immunotherapies. Experts discuss recent advances in our understanding of their biology in cancer as well as outstanding questions and potential therapeutic avenues., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
36. The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake.
- Author
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de Mingo Pulido Á, Hänggi K, Celias DP, Gardner A, Li J, Batista-Bittencourt B, Mohamed E, Trillo-Tinoco J, Osunmakinde O, Peña R, Onimus A, Kaisho T, Kaufmann J, McEachern K, Soliman H, Luca VC, Rodriguez PC, Yu X, and Ruffell B
- Subjects
- Animals, Biological Transport physiology, Cell Line, Cell Line, Tumor, Chemokines metabolism, Cytoplasm metabolism, Endocytosis physiology, Female, HEK293 Cells, Humans, Immunotherapy methods, Mice, Mice, Inbred C57BL, DNA metabolism, Dendritic Cells metabolism, Hepatitis A Virus Cellular Receptor 2 metabolism, Membrane Proteins metabolism, Nucleotidyltransferases metabolism, Signal Transduction physiology
- Abstract
Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. TIM-3 inhibits production of the chemokine CXCL9 by XCR1
+ classical dendritic cells (cDC1), thereby limiting antitumor immunity in mammary carcinomas. We found that increased CXCL9 expression by splenic cDC1s upon TIM-3 blockade required type I interferons and extracellular DNA. Chemokine expression as well as combinatorial efficacy of TIM-3 blockade and paclitaxel chemotherapy were impaired by deletion of Cgas and Sting. TIM-3 blockade increased uptake of extracellular DNA by cDC1 through an endocytic process that resulted in cytoplasmic localization. DNA uptake and efficacy of TIM-3 blockade required DNA binding by HMGB1, while galectin-9-induced cell surface clustering of TIM-3 was necessary for its suppressive function. Human peripheral blood cDC1s also took up extracellular DNA upon TIM-3 blockade. Thus, TIM-3 regulates endocytosis of extracellular DNA and activation of the cytoplasmic DNA sensing cGAS-STING pathway in cDC1s, with implications for understanding the mechanisms underlying TIM-3 immunotherapy., Competing Interests: Declaration of interests This work was supported in part by a sponsored research agreement with TESARO. J.K. is an employee of GSK and K.M. was an employee of TESARO. H.S. has received payments from Novartis International AG for consulting and advisory boards. B.R. has received payments from Merck & Co. and Roche Farma S.A. for consulting. H.S., V.C.L., P.C.R., and B.R. have courtesy faculty appointments at the University of South Florida, Tampa., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
37. Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma.
- Author
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Jain MD, Zhao H, Wang X, Atkins R, Menges M, Reid K, Spitler K, Faramand R, Bachmeier C, Dean EA, Cao B, Chavez JC, Shah B, Lazaryan A, Nishihori T, Hussaini M, Gonzalez RJ, Mullinax JE, Rodriguez PC, Conejo-Garcia JR, Anasetti C, Davila ML, and Locke FL
- Subjects
- Adult, Aged, Cytokines blood, Female, Ferritins blood, Humans, Lymphoma, B-Cell genetics, Lymphoma, B-Cell immunology, Male, Middle Aged, RNA, Neoplasm biosynthesis, Receptors, Chimeric Antigen, Treatment Failure, Tumor Burden, Young Adult, Biological Products immunology, Immunotherapy, Adoptive, Interferons physiology, Lymphoma, B-Cell therapy, Myeloid-Derived Suppressor Cells immunology, Tumor Escape
- Abstract
Axicabtagene ciloleucel (axi-cel) is a chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory large B-cell lymphoma (LBCL). This study evaluated whether immune dysregulation, present before CAR T-cell therapy, was associated with treatment failure. Tumor expression of interferon (IFN) signaling, high blood levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and high blood interleukin-6 and ferritin levels were each associated with a lack of durable response. Similar to other cancers, we found that in LBCL tumors, IFN signaling is associated with the expression of multiple checkpoint ligands, including programmed cell death-ligand 1, and these were higher in patients who lacked durable responses to CAR-T therapy. Moreover, tumor IFN signaling and blood M-MDSCs associated with decreased axi-cel expansion. Finally, patients with high tumor burden had higher immune dysregulation with increased serum inflammatory markers and tumor IFN signaling. These data support that immune dysregulation in LBCL promotes axi-cel resistance via multiple mechanistic programs: insufficient axi-cel expansion associated with both circulating M-MDSC and tumor IFN signaling, which also gives rise to expression of immune checkpoint ligands., (© 2021 by The American Society of Hematology.)
- Published
- 2021
- Full Text
- View/download PDF
38. Tumor-related stress regulates functional plasticity of MDSCs.
- Author
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Mandula JK and Rodriguez PC
- Subjects
- Cell Differentiation, Cell Line, Tumor, Endoplasmic Reticulum Stress immunology, Endoplasmic Reticulum Stress physiology, Humans, Immunosuppression Therapy methods, Myeloid Cells immunology, Myeloid-Derived Suppressor Cells metabolism, Myeloid-Derived Suppressor Cells physiology, Neoplasms metabolism, Reactive Oxygen Species metabolism, Signal Transduction immunology, Stress, Physiological immunology, Myeloid-Derived Suppressor Cells immunology, Neoplasms physiopathology, Stress, Physiological physiology
- Abstract
Myeloid-derived suppressor cells (MDSCs) impair protective anti-tumor immunity and remain major obstacles that stymie the effectiveness of promising cancer therapies. Diverse tumor-derived stressors galvanize the differentiation, intra-tumoral expansion, and immunomodulatory function of MDSCs. These tumor-associated 'axes of stress' underwrite the immunosuppressive programming of MDSCs in cancer and contribute to the phenotypic/functional heterogeneity that characterize tumor-MDSCs. This review discusses various tumor-associated axes of stress that direct MDSC development, accumulation, and immunosuppressive function, as well as current strategies aimed at overcoming the detrimental impact of MDSCs in cancer. To better understand the constellation of signals directing MDSC biology, we herein summarize the pivotal roles, signaling mediators, and effects of reactive oxygen/nitrogen species-related stress, chronic inflammatory stress, hypoxia-linked stress, endoplasmic reticulum stress, metabolic stress, and therapy-associated stress on MDSCs. Although therapeutic targeting of these processes remains mostly pre-clinical, intercepting signaling through the axes of stress could overcome MDSC-related immune suppression in tumor-bearing hosts., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
39. Targeted Therapy Given after Anti-PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity.
- Author
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Phadke MS, Chen Z, Li J, Mohamed E, Davies MA, Smalley I, Duckett DR, Palve V, Czerniecki BJ, Forsyth PA, Noyes D, Adeegbe DO, Eroglu Z, Nguyen KT, Tsai KY, Rix U, Burd CE, Chen YA, Rodriguez PC, and Smalley KSM
- Subjects
- Animals, Antineoplastic Agents chemistry, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Disease Models, Animal, Female, Imidazoles chemistry, Immunotherapy, Melanoma genetics, Melanoma immunology, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Molecular Targeted Therapy, Monomeric GTP-Binding Proteins genetics, Mutation, Oximes chemistry, Programmed Cell Death 1 Receptor antagonists & inhibitors, Proto-Oncogene Proteins B-raf genetics, Pyridones chemistry, Pyrimidines chemistry, Pyrimidinones chemistry, Skin Neoplasms genetics, Skin Neoplasms immunology, Sulfones chemistry, T-Lymphocytes, Regulatory immunology, Antineoplastic Agents therapeutic use, Melanoma drug therapy, Monomeric GTP-Binding Proteins antagonists & inhibitors, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Skin Neoplasms drug therapy
- Abstract
Immunotherapy (IT) and targeted therapy (TT) are both effective against melanoma, but their combination is frequently toxic. Here, we investigated whether the sequence of IT (anti-PD-1)→ TT (ceritinib-trametinib or dabrafenib-trametinib) was associated with improved antitumor responses in mouse models of BRAF- and NRAS -mutant melanoma. Mice with NRAS- mutant (SW1) or BRAF -mutant (SM1) mouse melanomas were treated with either IT, TT, or the sequence of IT→TT. Tumor volumes were measured, and samples from the NRAS -mutant melanomas were collected for immune-cell analysis, single-cell RNA sequencing (scRNA-seq), and reverse phase protein analysis (RPPA). scRNA-seq demonstrated that the IT→TT sequence modulated the immune environment, leading to increased infiltration of T cells, monocytes, dendritic cells and natural killer cells, and decreased numbers of tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells. Durable responses to the IT→TT sequence were dependent on T-cell activity, with depletion of CD8
+ , but not CD4+ , T cells abrogating the therapeutic response. An analysis of transcriptional heterogeneity in the melanoma compartment showed the sequence of IT→TT enriched for a population of melanoma cells with increased expression of MHC class I and melanoma antigens. RPPA analysis demonstrated that the sustained immune response induced by IT→TT suppressed tumor-intrinsic signaling pathways required for therapeutic escape. These studies establish that upfront IT improves the responses to TT in BRAF- and NRAS -mutant melanoma models., (©2021 American Association for Cancer Research.)- Published
- 2021
- Full Text
- View/download PDF
40. IgA transcytosis and antigen recognition govern ovarian cancer immunity.
- Author
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Biswas S, Mandal G, Payne KK, Anadon CM, Gatenbee CD, Chaurio RA, Costich TL, Moran C, Harro CM, Rigolizzo KE, Mine JA, Trillo-Tinoco J, Sasamoto N, Terry KL, Marchion D, Buras A, Wenham RM, Yu X, Townsend MK, Tworoger SS, Rodriguez PC, Anderson AR, and Conejo-Garcia JR
- Subjects
- Antibody Specificity, Antigens, CD immunology, Cell Line, Disease Progression, Female, Humans, Ovarian Neoplasms prevention & control, Receptors, Fc immunology, Signaling Lymphocytic Activation Molecule Family immunology, Tumor Microenvironment immunology, Antigens, Neoplasm immunology, Immunoglobulin A immunology, Ovarian Neoplasms immunology, Ovarian Neoplasms pathology, T-Lymphocytes, Cytotoxic immunology, Transcytosis immunology
- Abstract
Most ovarian cancers are infiltrated by prognostically relevant activated T cells
1-3 , yet exhibit low response rates to immune checkpoint inhibitors4 . Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6 , but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.- Published
- 2021
- Full Text
- View/download PDF
41. Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice.
- Author
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Harro CM, Perez-Sanz J, Costich TL, Payne KK, Anadon CM, Chaurio RA, Biswas S, Mandal G, Rigolizzo KE, Sprenger KB, Mine JA, Showe LC, Yu X, Liu K, Rodriguez PC, Pinilla-Ibarz J, Sokol L, and Conejo-Garcia JR
- Subjects
- Animals, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes pathology, Cell Line, Tumor, Humans, Methyltransferases metabolism, Mice, Mice, Transgenic, Sezary Syndrome metabolism, Sezary Syndrome pathology, Skin Neoplasms metabolism, Skin Neoplasms pathology, Enzyme Inhibitors pharmacology, Matrix Attachment Region Binding Proteins metabolism, Methyltransferases antagonists & inhibitors, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins metabolism, Sezary Syndrome drug therapy, Skin Neoplasms drug therapy
- Abstract
Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no known cure. Using conditional knockout mice, we found that ablation of the genomic organizer special AT-rich sequence-binding protein 1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition) restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with mycosis fungoides/Sézary syndrome, a set of incurable diseases.
- Published
- 2021
- Full Text
- View/download PDF
42. MEK inhibition reprograms CD8 + T lymphocytes into memory stem cells with potent antitumor effects.
- Author
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Verma V, Jafarzadeh N, Boi S, Kundu S, Jiang Z, Fan Y, Lopez J, Nandre R, Zeng P, Alolaqi F, Ahmad S, Gaur P, Barry ST, Valge-Archer VE, Smith PD, Banchereau J, Mkrtichyan M, Youngblood B, Rodriguez PC, Gupta S, and Khleif SN
- Subjects
- Animals, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology, Cell Cycle drug effects, Humans, Immunologic Memory immunology, Mice, Mice, Inbred C57BL, Mitochondria drug effects, Receptors, Antigen, T-Cell physiology, Tumor Microenvironment, Antineoplastic Agents pharmacology, CD8-Positive T-Lymphocytes drug effects, Immunologic Memory drug effects, Immunotherapy, Adoptive, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Neoplasms therapy, Stem Cells cytology
- Abstract
Regenerative stem cell-like memory (T
SCM ) CD8+ T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces TSCM that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced TSCM cells exhibited plasticity and loci-specific profiles similar to bona fide TSCM isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8+ T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8+ T cell reprogramming into TSCM that acts as a reservoir for effector T cells with potent therapeutic characteristics.- Published
- 2021
- Full Text
- View/download PDF
43. BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells.
- Author
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Payne KK, Mine JA, Biswas S, Chaurio RA, Perales-Puchalt A, Anadon CM, Costich TL, Harro CM, Walrath J, Ming Q, Tcyganov E, Buras AL, Rigolizzo KE, Mandal G, Lajoie J, Ophir M, Tchou J, Marchion D, Luca VC, Bobrowicz P, McLaughlin B, Eskiocak U, Schmidt M, Cubillos-Ruiz JR, Rodriguez PC, Gabrilovich DI, and Conejo-Garcia JR
- Subjects
- Animals, Antibodies, Monoclonal therapeutic use, Antigens, CD genetics, Butyrophilins genetics, Female, Humans, Immunotherapy methods, Mice, Mice, Transgenic, Receptors, Antigen, T-Cell, alpha-beta immunology, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antigens, CD immunology, Butyrophilins antagonists & inhibitors, Butyrophilins immunology, Intraepithelial Lymphocytes immunology, Ovarian Neoplasms immunology, Ovarian Neoplasms therapy
- Abstract
Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate αβ and γδ T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive αβ T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of αβ T cell effector activity and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1
+ cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αβ and γδ T cells and may present a treatment strategy for tumors resistant to existing immunotherapies., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2020
- Full Text
- View/download PDF
44. Kindlin-3 gives patrolling monocytes a strong grip.
- Author
-
Conejo-Garcia JR and Rodriguez PC
- Subjects
- Hand Strength, Humans, Phagocytosis, Monocytes, Neoplasms
- Published
- 2020
- Full Text
- View/download PDF
45. The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling.
- Author
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Mohamed E, Sierra RA, Trillo-Tinoco J, Cao Y, Innamarato P, Payne KK, de Mingo Pulido A, Mandula J, Zhang S, Thevenot P, Biswas S, Abdalla SK, Costich TL, Hänggi K, Anadon CM, Flores ER, Haura EB, Mehrotra S, Pilon-Thomas S, Ruffell B, Munn DH, Cubillos-Ruiz JR, Conejo-Garcia JR, and Rodriguez PC
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Carcinoma, Lewis Lung genetics, Carcinoma, Lewis Lung metabolism, Carcinoma, Lewis Lung pathology, Carcinoma, Ovarian Epithelial genetics, Carcinoma, Ovarian Epithelial metabolism, Carcinoma, Ovarian Epithelial pathology, Female, Humans, Immunosuppression Therapy, Interferon-alpha genetics, Interferon-alpha immunology, Interferon-beta genetics, Interferon-beta immunology, Male, Melanoma, Experimental genetics, Melanoma, Experimental metabolism, Melanoma, Experimental pathology, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria immunology, Mitochondria metabolism, Myeloid-Derived Suppressor Cells immunology, Myeloid-Derived Suppressor Cells pathology, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 immunology, Receptors, Interferon genetics, Receptors, Interferon immunology, Signal Transduction, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms pathology, Unfolded Protein Response immunology, eIF-2 Kinase deficiency, eIF-2 Kinase genetics, Carcinoma, Lewis Lung immunology, Carcinoma, Ovarian Epithelial immunology, Gene Expression Regulation, Neoplastic, Melanoma, Experimental immunology, Membrane Proteins immunology, Skin Neoplasms immunology, eIF-2 Kinase immunology
- Abstract
The primary mechanisms supporting immunoregulatory polarization of myeloid cells upon infiltration into tumors remain largely unexplored. Elucidation of these signals could enable better strategies to restore protective anti-tumor immunity. Here, we investigated the role of the intrinsic activation of the PKR-like endoplasmic reticulum (ER) kinase (PERK) in the immunoinhibitory actions of tumor-associated myeloid-derived suppressor cells (tumor-MDSCs). PERK signaling increased in tumor-MDSCs, and its deletion transformed MDSCs into myeloid cells that activated CD8
+ T cell-mediated immunity against cancer. Tumor-MDSCs lacking PERK exhibited disrupted NRF2-driven antioxidant capacity and impaired mitochondrial respiratory homeostasis. Moreover, reduced NRF2 signaling in PERK-deficient MDSCs elicited cytosolic mitochondrial DNA elevation and, consequently, STING-dependent expression of anti-tumor type I interferon. Reactivation of NRF2 signaling, conditional deletion of STING, or blockade of type I interferon receptor I restored the immunoinhibitory potential of PERK-ablated MDSCs. Our findings demonstrate the pivotal role of PERK in tumor-MDSC functionality and unveil strategies to reprogram immunosuppressive myelopoiesis in tumors to boost cancer immunotherapy., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
46. c-Maf: a bad influence in the education of macrophages.
- Author
-
Conejo-Garcia JR and Rodriguez PC
- Subjects
- Humans, Macrophages, MafF Transcription Factor, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms
- Abstract
Tumor-associated macrophages (TAMs) represent the most abundant hematopoietic cell type in the solid tumor microenvironment. TAMs drive T cell inhibition, promote angiogenesis, and produce tumor growth factors. Although they can paradoxically exert antitumor activity and prime protective immunity, the pathways driving this phenotype remain unclear. In this issue of the JCI, Liu and colleagues identified the c-Maf transcription factor as a master regulator of protumoral TAM polarization. The authors found that c-Maf promoted TAMs' immunosuppressive activity, governed their metabolic programming, and drove expression of the macrophage differentiation protein, CSF1R. Further, inhibiting c-Maf in myeloid progenitors, and consequent myeloid-lineage cells, including TAMs, delayed tumor growth. Importantly, β-glucan treatment reduced c-MAF expression in macrophages and monocytes from patients with non-small cell lung cancer (NSCLC) where c-MAF is overexpressed. These results reveal mechanisms whereby myeloid cells drive human cancer progression by thwarting protective immunity and could lead to immunotherapy for most solid malignancies.
- Published
- 2020
- Full Text
- View/download PDF
47. CD73 on cancer-associated fibroblasts enhanced by the A 2B -mediated feedforward circuit enforces an immune checkpoint.
- Author
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Yu M, Guo G, Huang L, Deng L, Chang CS, Achyut BR, Canning M, Xu N, Arbab AS, Bollag RJ, Rodriguez PC, Mellor AL, Shi H, Munn DH, and Cui Y
- Subjects
- Adenosine metabolism, Adenosine A2 Receptor Antagonists pharmacology, Animals, Cancer-Associated Fibroblasts drug effects, Cancer-Associated Fibroblasts pathology, Cell Line, Tumor, Colorectal Neoplasms metabolism, Disease Progression, Drug Synergism, Hematopoietic Stem Cells metabolism, Humans, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Inbred C57BL, Models, Biological, Neutralization Tests, Transcriptome genetics, Treatment Outcome, Tumor Microenvironment, Up-Regulation, 5'-Nucleotidase metabolism, Cancer-Associated Fibroblasts metabolism, Colorectal Neoplasms immunology, Colorectal Neoplasms pathology, Receptor, Adenosine A2B metabolism
- Abstract
CD73, an ecto-5'-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A
2A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73hi population in human colorectal cancers (CRCs) and two CD73- murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A2B receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A2A and A2B pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A2B -mediated ADO-CAF-CD73 feedforward circuit and A2A -mediated immune suppression is crucial for improving therapeutic outcomes.- Published
- 2020
- Full Text
- View/download PDF
48. AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells.
- Author
-
Trillo-Tinoco J, Sierra RA, Mohamed E, Cao Y, de Mingo-Pulido Á, Gilvary DL, Anadon CM, Costich TL, Wei S, Flores ER, Ruffell B, Conejo-Garcia JR, and Rodriguez PC
- Subjects
- AMP-Activated Protein Kinases metabolism, Animals, Carcinoma, Ovarian Epithelial metabolism, Cell Differentiation immunology, Female, Humans, Mice, Myeloid-Derived Suppressor Cells metabolism, Neoplasms, Experimental metabolism, Tumor Escape immunology, AMP-Activated Protein Kinases immunology, Carcinoma, Ovarian Epithelial immunology, Myeloid-Derived Suppressor Cells immunology, Neoplasms, Experimental immunology, Tumor Microenvironment immunology
- Abstract
Myeloid-derived suppressor cells (MDSC) represent a primary mechanism of immune evasion in tumors and have emerged as a major obstacle for cancer immunotherapy. The immunoinhibitory activity of MDSC is tightly regulated by the tumor microenvironment and occurs through mechanistic mediators that remain unclear. Here, we elucidated the intrinsic interaction between the expression of AMP-activated protein kinase alpha (AMPKα) and the immunoregulatory activity of MDSC in tumors. AMPKα signaling was increased in tumor-MDSC from tumor-bearing mice and patients with ovarian cancer. Transcription of the Ampkα1-coding gene, Prkaa1 , in tumor-MDSC was induced by cancer cell-derived granulocyte-monocyte colony-stimulating factor (GM-CSF) and occurred in a Stat5-dependent manner. Conditional deletion of Prkaa1 in myeloid cells, or therapeutic inhibition of Ampkα in tumor-bearing mice, delayed tumor growth, inhibited the immunosuppressive potential of MDSC, triggered antitumor CD8
+ T-cell immunity, and boosted the efficacy of T-cell immunotherapy. Complementarily, therapeutic stimulation of AMPKα signaling intrinsically promoted MDSC immunoregulatory activity. In addition, Prkaa1 deletion antagonized the differentiation of monocytic-MDSC (M-MDSC) to macrophages and re-routed M-MDSC, but not granulocytic-MDSC (PMN-MDSC), into cells that elicited direct antitumor cytotoxic effects through nitric oxide synthase 2-mediated actions. Thus, our results demonstrate the primary role of AMPKα1 in the immunosuppressive effects induced by tumor-MDSC and support the therapeutic use of AMPK inhibitors to overcome MDSC-induced T-cell dysfunction in cancer. SIGNIFICANCE: AMPKα1 regulates the immunosuppressive activity and differentiation of tumor-MDSC, suggesting AMPK inhibition as a potential therapeutic strategy to restore protective myelopoiesis in cancer., (©2019 American Association for Cancer Research.)- Published
- 2019
- Full Text
- View/download PDF
49. Polyphenol-rich extract induces apoptosis with immunogenic markers in melanoma cells through the ER stress-associated kinase PERK.
- Author
-
Prieto K, Cao Y, Mohamed E, Trillo-Tinoco J, Sierra RA, Urueña C, Sandoval TA, Fiorentino S, Rodriguez PC, and Barreto A
- Abstract
Polyphenols elicit antitumor activities, in part, through the induction of anti- or pro-oxidant effects in cancer cells which promote priming of protective anti-tumor immunity. We recently characterized a polyphenol-rich extract from Caesalpinia spinosa (P2Et) that stimulates in vivo antitumor responses against breast and melanoma tumor models via the promotion of immunogenic cancer cell death (ICD). However, the primary mediators whereby P2Et promotes ICD remained unknown. Here, we sought to elucidate the role that severe endoplasmic reticulum (ER) stress plays in mediating P2Et-induced apoptosis and ICD in murine melanoma cells. Our findings demonstrate a substantial selective induction of specific ER-stress mediators in B16-F10 melanoma cells treated with P2Et. While knockout of the ER stress-associated PKR-like ER kinase (PERK) prevented induction of apoptosis and expression of ICD markers in P2Et-treated cells, deletion of X-box binding protein 1 (Xbp1) did not. P2Et-driven activation of PERK in melanoma cells was found to promote ER-calcium release, disrupt mitochondrial membrane potential, and trigger upregulation of ICD drivers, surface calreticulin expression, and extracellular release of ATP and HMGB1. Notably, calcium release inhibition, but not targeting of PERK-driven integrated stress responses, prevented P2Et-induced apoptosis. Collectively, these results underline the central role of PERK-directed calcium release in mediating the antitumor and immunogenic actions of P2Et in melanoma cells., Competing Interests: Conflict of interestSF, TS and CU are inventors of a granted patent related to P2Et. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2019
- Full Text
- View/download PDF
50. Publisher Correction: ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression.
- Author
-
Cao Y, Trillo-Tinoco J, Sierra RA, Anadon C, Dai W, Mohamed E, Cen L, Costich TL, Magliocco A, Marchion D, Klar R, Michel S, Jaschinski F, Reich RR, Mehrotra S, Cubillos-Ruiz JR, Munn DH, Conejo-Garcia JR, and Rodriguez PC
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2019
- Full Text
- View/download PDF
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