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1. Impaired IL-23-dependent induction of IFN-gamma underlies mycobacterial disease in patients with inherited TYK2 deficiency

Author

Masato Ogishi, Andrés Augusto Arias, Rui Yang, Ji Eun Han, Peng Zhang, Darawan Rinchai, Joshua Halpern, Jeanette Mulwa, Narelle Keating, Maya Chrabieh, Candice Lainé, Yoann Seeleuthner, Noé Ramírez-Alejo, Nioosha Nekooie-Marnany, Andrea Guennoun, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Sara S. Kilic, Yoshiyuki Minegishi, Stephan Ehl, Petra Kaiser-Labusch, Yasemin Kendir-Demirkol, Flore Rozenberg, Abderrahmane Errami, Shen-Ying Zhang, Qian Zhang, Jonathan Bohlen, Quentin Philippot, Anne Puel, Emmanuelle Jouanguy, Zahra Pourmoghaddas, Shahrzad Bakhtiar, Andre M. Willasch, Gerd Horneff, Genevieve Llanora, Lynette P. Shek, Louis Y.A. Chai, Sen Hee Tay, Hamid H. Rahimi, Seyed Alireza Mahdaviani, Serdar Nepesov, Aziz A. Bousfiha, Emine Hafize Erdeniz, Adem Karbuz, Nico Marr, Carmen Navarrete, Mehdi Adeli, Lennart Hammarstrom, Hassan Abolhassani, Nima Parvaneh, Saleh Al Muhsen, Mohammed F. Alosaimi, Fahad Alsohime, Maryam Nourizadeh, Mostafa Moin, Rand Arnaout, Saad Alshareef, Jamila El-Baghdadi, Ferah Genel, Roya Sherkat, Ayça Kiykim, Esra Yücel, Sevgi Keles, Jacinta Bustamante, Laurent Abel, Jean-Laurent Casanova, and Stéphanie Boisson-Dupuis

Subjects
TYK2 Kinase, Interferon-gamma, Human Cells, Immunology, Immunology and Allergy, Humans, Immunodeficiency, TYK2, Interleukin-23, Job Syndrome
Abstract

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling. ANRS Nord-Sud ; CIBSS ; CODI ; Comité para el Desarrollo de la Investigación ; Fulbright Future Scholarship

Published
2022

2. Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents

Author

Rui Yang, Rubén Martínez-Barricarte, Janet Markle, Franck Rapaport, Stuart G. Tangye, Mathieu Bourgey, David Langlais, Anne Puel, Aziz Belkadi, Masato Ogishi, Simon J. Pelham, Jean-Laurent Casanova, Bertrand Boisson, Cindy S. Ma, Vivien Béziat, Eman Abou Moussa, Jérémie Rosain, Laurent Abel, Tomi Lazarov, Serkan Belkaya, Fatima Ailal, Ibtihal Benhsaien, Coralie Briand, Alessandro Plebani, Romain Lévy, Frederic Geissmann, Caroline Deswarte, Andrea Guennoun, Luis R. Saraiva, Tanwir Habib, Mehdi Emam, Vassilios Lougaris, Philippe Gros, Yu Jerry Zhou, Ahmed Aziz Bousfiha, Geetha Rao, Kathryn Payne, Sylvain Breton, Ai Ing Lim, Kang Liu, Kunihiko Moriya, Danielle T. Avery, Bénédicte Neven, Nico Marr, Jacinta Bustamante, Mélanie Migaud, and James P. Di Santo

Subjects
Myeloid, Primary Immunodeficiency Diseases, Naive B cell, Adaptive Immunity, Biology, Lymphocyte Activation, Consanguinity, Immunity, medicine, Humans, Protein Isoforms, Myeloid Cells, Lymphocytes, Child, B cell, CD86, Host Microbial Interactions, Homozygote, Hematopoietic Stem Cell Transplantation, General Medicine, Acquired immune system, Immunity, Innate, Proto-Oncogene Proteins c-rel, medicine.anatomical_structure, Mutation, Immunology, Female, Genes, rel, REL, CD8, Research Article
Abstract

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8(+) T cells, memory CD4(+) T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4(+) T cells. In naive CD4(+) T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient’s naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

Published
2021
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3. STK4 deficiency underlies impaired interferon signaling and T cell immunity

Author

Khalid A. Fakhro, Fatima Al Ali, Mehdi Adeli, Salim Bougarn, Alya Al-Shakaki, Amel Hassan, Debra O. Prosser, Eman Al Maslamani, Rafah Mackeh, Donald R. Love, Amal Al-Naimi, Taushif Khan, Manar Ata, Mohammed Yousuf Karim, Ronald G. Crystal, Bernice Lo, Waleed Aamer, Nico Marr, Khawla Al-Darwish, Ibrahim A. Janahi, Qian Zhang, Amjad Tuffaha, Mahbuba Rahman, Tanwir Habib, Amal Robay, Mohammad Janahi, Andrea Guennoun, and Evonne Chin-Smith

Subjects
Text mining, business.industry, Interferon, Immunology, medicine, T cell immunity, Biology, business, medicine.drug
Abstract

Purpose. Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency. The extent to which STK4 deficiency impairs immune signaling and host defenses is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C>T, p.Arg291*) found in a pediatric patient by comparing the patient’s innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls.Methods. The genetic etiology was identified by whole genome sequencing and confirmed by Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA and polychromatic flow cytometry. Finally, antibody responses were delinated by ELISA and phage immunoprecipitation-sequencing.Results. The affected patient exhibited partial loss of STK4 expression and complete loss of STK4 function. The patient suffered from recurrent viral and bacterial infections, most notably persistent Epstein-Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormalities to the fractions of T-cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient’s whole blood and PBMC samples were reminiscent of dysregulated interferon signaling, impaired T immunity and increased T-cell apoptosis. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B-cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpesvirus antigens.Conclusion. Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.

Published
2021
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4. Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β

Author

Marco Ritelli, Harry C. Dietz, Danielle T. Avery, Bertrand Boisson, Soraya Boucherit, Lucie Grodecká, Stuart G. Tangye, Romain Lévy, Kathryn Payne, Tomáš Freiberger, Sophie Cypowyj, Juan Li, Valérie Cormier-Daire, Nicoletta Zoppi, Laurent Abel, Geetha Rao, Vivien Béziat, Andrea Guennoun, Benedetta Bigio, Maya Chrabieh, Salim Bougarn, Marina Colombi, Lei Shang, Emilie Corvilain, Yuval Itan, Anne Puel, Franck Rapaport, Nico Marr, Fransiska Malfait, Delfien Syx, Mélanie Migaud, Tanwir Habib, Sabri Boughorbel, Jean-Laurent Casanova, and Cindy S. Ma

Subjects
Male, 0301 basic medicine, Connective Tissue Disorder, MAPK8, Immunology, Mucocutaneous zone, Connective tissue, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, medicine, Humans, Mitogen-Activated Protein Kinase 8, Chronic mucocutaneous candidiasis, Connective Tissue Diseases, Alleles, Cells, Cultured, business.industry, Candidiasis, Chronic Mucocutaneous, Interleukin-17, General Medicine, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, Signal transduction, Haploinsufficiency, business
Abstract

Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-β-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients' fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients' TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β-responsive pathway and further accounting for the patients' CMC. Consistently, the patients' fibroblasts displayed impaired JNK1- and c-Jun/ATF-2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of TGFBR2 or SMAD3, further accounting for the patients' complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida and for the TGF-β-dependent homeostasis of connective tissues.

Published
2019
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5. Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant

Author

Durga Sivanesan, Cindy S. Ma, Zafer Caliskaner, Katia Abarca, Jaime Inostroza, Hicham Souhi, Nicholas Hernandez, Stephen W. Michnick, Alix Checchi, Tayfun Ozcelik, Ahmed Abid, Rubén Martínez-Barricarte, Noé Ramírez-Alejo, Adil Zegmout, Esra Hazar Sayar, Nico Marr, Ismail Reisli, Lluis Quintana-Murci, Jamila El-Baghdadi, Bernhard Fleckenstein, Hassan Abolhassani, Jacinta Bustamante, Ingrid Müller-Fleckenstein, Ismail Abderahmani Rhorfi, Antonio Condino-Neto, Jose Antonio Tavares de Albuquerque, Rodrigo Naves, Dimitry N. Krementsov, Beatriz Tavares Costa-Carvalho, Sandra Pellegrini, Aurélie Cobat, Robert Fisch, Michael J. Ciancanelli, Gaspard Kerner, Lorena Orozco, Geetha Rao, Jeanette Mulwa, Hans D. Ochs, Stuart G. Tangye, Fabienne Jabot-Hanin, Patricia García, Frederic Geissmann, Stéphanie Boisson-Dupuis, Humberto García-Ortiz, Zhi Li, Tomi Lazarov, Bertrand Boisson, Hicham Naji Amrani, María Elvira Balcells, Caroline Deswarte, Andrea Guennoun, Alexis Strickler, Carolyn C. Jackson, Sevgi Pekcan, Janet Markle, Joshua Halpern, Jean-Laurent Casanova, Cory Teuscher, Che Kang Lim, Anne Puel, Yuval Itan, Lennart Hammarström, Matthieu Bouaziz, Etienne Patin, Laurent Abel, Qian Zhang, Kathryn Payne, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Garvan Institute of Medical Research [Darlinghurst, Australia], Laboratory for the Modeling of Biological and Socio-technical Systems [Boston] (MoBS), Northeastern University [Boston], Memorial Sloane Kettering Cancer Center [New York], Laboratory of Genetic Medicine & Immunology, Weill Cornell Medicine [Qatar], Bases de données et traitement des langues naturelles (BDTLN), Laboratoire d'Informatique Fondamentale et Appliquée de Tours (LIFAT), Université de Tours-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, Sidra Medicine [Doha, Qatar], Tehran University of Medical Sciences (TUMS), Infectious Diseases Department, School of Medicine, Pontificia Universidad Católica de Chile (UC), Institute of Biomedical Sciences - Department of Immunology [Sao Paulo], University of São Paulo (USP), Hosp Puerto Montt, University of Washington [Seattle], Selcuk University, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Garvan Institute for Medical Research, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], The Laboratory of Human Genetics of Infectious Diseases was supported, in part, by grants from the French National Agency for Research (ANR) under the 'Investissement d’avenir' program (grant no. ANR-10-IAHU-01), the TBPATHGEN project (grant no. ANR-14-CE14-0007-01), the GENMSMD project (grant no. ANR-16-CE17-0005-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (grant no. ANR-10-LABX-62-IBEID), the European Research Council (ERC, grant no. ERC-2010-AdG-268777), the SCOR Corporate Foundation for Science, the St. Giles Foundation, the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), NIH (grant no. UL1TR001866), the National Institute of Allergy and Infectious Diseases (NIAID) (grant nos. 5R01AI089970, 5R37AI095983, 5U01AI088685, and 5U19AI111143), and The Rockefeller University. Work at the Cytokine Signaling Unit was supported, in part, by a grant from Fondation de la Recherche Médicale to S. Pellegrini (grant no. DEQ20170336741). J.B. was supported by Support of Clinical Research (grant no. SRC2017). C.S.M. and S.G.T. were supported by fellowships and grants from the National Health and Medical Research Council of Australia and the Office of Health and Medical Research of the Government of New South Wales (Australia). M.E.B. was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT, grant no. 1171570) A.C.-N. was supported by Fundação de Amparo a Pesquisa do Estado e de São Paulo (Fapesp) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). N.R.-A. was supported by fellowships from Consejo Nacional de Ciencia y Tecnología (CONACYT, grant no. 264011) and the Stony Wold-Herbert Fund. Z.L. was supported by the CNRS. J. Markle was supported by the Charles H. Revson Senior Fellowship in Biomedical Sciences and NIAID grant K99AI27932. C.C.J. was the Damon Runyon-Richard Lumsden Foundation Physician Scientist supported by the Damon Runyon Cancer Research Foundation (PST-03-15). H.D.O. was supported by the Jeffrey Modell Foundation. N.H. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH under award no. T32GM007739 to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. The content of this study is the sole responsibility of the authors and does not necessarily represent the official views of the NIH. The Yale Center for Mendelian Genomics (UM1HG006504) is funded by the National Human Genome Research Institute. Funds were also provided by the National Heart, Lung, and Blood Institute. The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0007,TBPATHGEN,Dissection de la pathogenèse de la tuberculose par l'identification de défauts monogéniques de l'immunité dans les formes pédiatriques sévères de la maladie(2014), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 268777,EC:FP7:ERC,ERC-2010-AdG_20100317,GENTB(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Garvan Institute of medical research, Université de Tours (UT)-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT)-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Universidade de São Paulo = University of São Paulo (USP), Özçelik, Tayfun, Li, Zhi, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Appel à projets générique - Dissection de la pathogenèse de la tuberculose par l'identification de défauts monogéniques de l'immunité dans les formes pédiatriques sévères de la maladie - - TBPATHGEN2014 - ANR-14-CE14-0007 - Appel à projets générique - VALID, Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme - - GENMSMD2016 - ANR-16-CE17-0005 - AAPG2016 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Human Genetics of Tuberculosis - GENTB - - EC:FP7:ERC2011-06-01 - 2016-05-31 - 268777 - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]

Subjects
0301 basic medicine, Tuberculosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Immunology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Immunity, medicine, Missense mutation, Allele, Receptor, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, General Medicine, medicine.disease, 3. Good health, 030104 developmental biology, Cytokine, Tyrosine kinase 2, [SDV.IMM]Life Sciences [q-bio]/Immunology, IMUNOGENÉTICA, 030215 immunology
Abstract

International audience; Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 × 10-8; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

Published
2018
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6. Harnessing the immune system for the treatment of melanoma: current status and future prospects

Author

Cristina Maccalli, Heba Sidahmed, Davide Bedognetti, Barbara Seliger, Andrea Guennoun, and Francesco M. Marincola

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Combination therapy, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Immunology, Antineoplastic Agents, Disease, B7-H1 Antigen, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Animals, Humans, Immunologic Factors, Immunology and Allergy, Combined Modality Therapy, CTLA-4 Antigen, Molecular Targeted Therapy, Melanoma, business.industry, Abscopal effect, Immunotherapy, medicine.disease, Immune checkpoint, 030104 developmental biology, Immune System, 030220 oncology & carcinogenesis, business
Abstract

When malignant melanoma is diagnosed early, surgical resection is the intervention of choice and is often curative, but many patients present with unresectable disease at later stages. Due to its complex etiology paired with well-documented chemoresistance and high metastatic potential, patients with advanced melanoma had a poor prognosis, and the treatment of this disease remained unsatisfactory for many years. Recently, targeted therapy, immune checkpoint inhibition, or combinatory approaches have revolutionized the therapeutic options of melanoma allowing considerable improvement in disease control and survival. In this review we will summarize these novel therapeutic strategies with particular focus on combinatory immunotherapies and further discuss recent data derived from immunogenomic studies and potential options to improve the therapeutic efficacy of immune modulatory approaches.

Published
2016

7. Comprehensive molecular characterization of human adipocytes reveals a transient brown phenotype

Author

Vladimir Zilberfarb, Melissa Kazantzis, Lotfi Chouchane, Remy Thomas, Konduru S Sastry, Daniel Tews, Mouaadh Abdelkarim, Andrea Guennoun, Martin Wabitsch, Arthur Donny Strosberg, Laboratory of Genetic Medicine & Immunology, Weill Cornell Medical College in Qatar, Center for Diabetes and Metabolic Diseases, The Scripps Research Institute, Department of Paediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetology, Department of Physiology, King Saud University [Riyadh] (KSU), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Department of Infectology, Weill Cornell Medicine [Qatar], Scripps Research Institute, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Scripps Research Institute [La Jolla, San Diego], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and BMC, BMC

Subjects
Leptin, Cellular differentiation, [SDV]Life Sciences [q-bio], Adipocytes, White, Ion Channels, Lipid droplet, Gene expression, Brown adipose tissue, Adipocytes, Cells, Cultured, Uncoupling Protein 1, Medicine(all), Adipogenesis, Non-shivering thermogenesis, High-Throughput Nucleotide Sequencing, Cell Differentiation, General Medicine, Phenotype, Thermogenin, Cell biology, Mitochondria, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Adipocytes, Brown, Adiponectin, medicine.medical_specialty, DNA, Complementary, WAT, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, Mitochondrial Proteins, Beige adipocytes, Internal medicine, medicine, Humans, RNA, Messenger, Obesity, Electron Transport Complex I, Biochemistry, Genetics and Molecular Biology(all), Sequence Analysis, RNA, Research, Gene Expression Profiling, BAT, SGBS cells, Oxygen, Endocrinology, Gene Expression Regulation, Microscopy, Fluorescence, Human adipocytes
Abstract

Background Functional brown adipose tissue (BAT), involved in energy expenditure, has recently been detected in substantial amounts in adults. Formerly overlooked BAT has now become an attractive anti-obesity target. Methods and results Molecular characterization of human brown and white adipocytes, using a myriad of techniques including high-throughput RNA sequencing and functional assays, showed that PAZ6 and SW872 cells exhibit classical molecular and phenotypic markers of brown and white adipocytes, respectively. However, the pre-adipocyte cell line SGBS presents a versatile phenotype. A transit expression of classical brown markers such as UCP1 and PPARγ peaked and declined at day 28 post-differentiation initiation. Conversely, white adipocyte markers, including Tcf21, showed reciprocal behavior. Interestingly, leptin levels peaked at day 28 whereas the highest adiponectin mRNA levels were detected at day 14 of differentiation. Phenotypic analysis of the abundance and shape of lipid droplets were consistent with the molecular patterns. Accordingly, the oxidative capacity of SGBS adipocytes peaked on differentiation day 14 and declined progressively towards differentiation day 28. Conclusions Our studies have unveiled a new phenotype of human adipocytes, providing a tool to identify molecular gene expression patterns and pathways involved in the conversion between white and brown adipocytes. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0480-6) contains supplementary material, which is available to authorized users.

Published
2015
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8. Autophagy Retards Inflammatory Mrna Decay And Elicits A White Phenotype During Adipocyte Maturation

Author

Lotfi Chouchane, Andrea Guennoun, Remy Thomas, and Jingxuan Shan

Subjects
medicine.medical_specialty, Autophagy, Lipid metabolism, Biology, Phenotype, chemistry.chemical_compound, Endocrinology, MRNA Sequencing, chemistry, Adipocyte, Internal medicine, Lipid droplet, Gene expression, medicine, Gene silencing
Abstract

Background: Recently, the role of autophagy in glucose and lipid metabolism has been emerging. Mice experiments showed that autophagy deficiency could prevent diet-induced obesity, characterized by less fat and a browning phenotype of white adipocyte (WAT). However, the underlying molecular mechanism is not well explored and the data from human are limited. Method: The mRNA sequencing data of undifferentiated and differentiated human adipocyte cell lines, including two white adipocyte (WAT) and one brown adipocyte (BAT) were included in our analysis. Gene expression was reduced by RNA interference in human adipocyte and was enhanced by glucocorticoid, respectively. Qualifying the lipid droplet content and quantifying the adipolysis and differentiation marker expression were applied to evaluate WAT differentiation. LC3 was used as a marker to examine autophagy function of adipocyte. Result: we found a remarkable feature of adipocyte differentiation that inflammation signaling was significantly strengthened during WAT maturation, but not during BAT maturation. The alteration of Zinc Finger protein 36 (ZFP36), which mediates the decay of mRNA transcripts of inflammation molecules, obviously affected the phenotype of mature WAT: silencing of ZFP36 gene resulted in a more whitening phenotype and induction of ZFP36 resulted in a browning phenotype. ZFP36 activity was associated with p38 MAPK signaling that was regulated by autophagy. Conclusion: ZFP36 links autophagy to the determination of mature adipocyte phenotype. Therefore, ZFP36 is a potential target to prevent obesity and improve glucose and lipid metabolism.

Published
2014
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