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11 results on '"Yuting Ma"'

1. Pro-necrotic molecules impact local immunosurveillance in human breast cancer

Author

Gautier Stoll, Yuting Ma, Heng Yang, Oliver Kepp, Laurence Zitvogel, and Guido Kroemer

Subjects
apoptosis, immunogenic cell death, immunosurveillance, necrosis, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Necrosis culminates in spilling cellular content through the permeabilized plasma membrane, thereby releasing potentially immunostimulatory molecules in the pericellular space of dead cells. Accordingly, molecules involved in necroptotic signaling, such as receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase-like (MLKL) have been found to stimulate anticancer immune responses in mouse models of chemotherapy. mRNAs encoding prominent pro-necrotic gene products (RIPK1, RIPK3, MLKL, PGAM5 and DFNA5) were correlated with immune-related metagenes in several cancer types (breast, colorectal, lung, ovary, melanoma), revealing the strongest associations in breast cancer. In two independent breast cancer cohorts, the expression of MLKL and DFNA5 was decreased at the mRNA levels in tumor as compared with normal tissues. Moreover, MLKL expression exhibited a strong positive correlation with genes reflecting the presence of B, NK and T lymphocytes in the tumor bed, in multiple distinct breast cancer subtypes. In contrast, the positive correlation between RIPK3 and lymphoid cells was restricted to HER2+ and triple negative/basal-like breast cancer. Moreover, the expression of DFNA5, which mediates post-apoptotic secondary necrosis, mostly correlated with the monocytic lineage and macrophages in ER+/luminal A breast cancers. MLKL (and to some extent RIPK1 and RIPK3) was strongly associated with the local expression of genes involved in interferon-α and interferon-γ responses. Altogether, these results support the idea that pro-necrotic signaling facilitates intratumoral immune responses in human breast cancer.

Published
2017
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2. Soluble uric acid induces myocardial damage through activating the NLRP3 inflammasome

Author

Jun Zhang, Guan-Li Wang, Shaowei Li, Yuanfang Ma, Guangchao Liu, Hao Zhang, Yuting Ma, Wang Yaohui, Meichen Liu, Run Cao, Shulian Li, Hailong Zhang, and Yue Cao

Subjects
0301 basic medicine, UCP2, TLR6/NF‐κB signal pathway, Inflammasomes, Caspase 1, Apoptosis, Models, Biological, Mitochondria, Heart, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, myocardial damage, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Secretion, Myocytes, Cardiac, Hyperuricemia, soluble uric acid, Gene knockdown, integumentary system, Ventricular Remodeling, Myocardium, NF-kappa B, Inflammasome, Cell Biology, Original Articles, medicine.disease, NLRP3 inflammasome, Cell biology, Rats, Uric Acid, 030104 developmental biology, Toll-Like Receptor 6, chemistry, 030220 oncology & carcinogenesis, TLR6, Gene Knockdown Techniques, Molecular Medicine, Uric acid, Original Article, Lysosomes, Reactive Oxygen Species, medicine.drug, Signal Transduction
Abstract

Uric acid crystal is known to activate the NLRP3 inflammasome and to cause tissue damages, which can result in many diseases, such as gout, chronic renal injury and myocardial damage. Meanwhile, soluble uric acid (sUA), before forming crystals, is also related to these diseases. This study was carried out to investigate whether sUA could also activate NLRP3 inflammasome in cardiomyocytes and to analyse the mechanisms. The cardiomyocyte activity was monitored, along with the levels of mature IL‐1β and caspase‐1 from H9c2 cells following sUA stimulus. We found that sUA was able to activate NLRP3 inflammasome, which was responsible for H9c2 cell apoptosis induced by sUA. By elevating TLR6 levels and then activating NF‐κB/p65 signal pathway, sUA promoted NLRP3, pro‐caspase 1 and pro‐IL‐1β production and provided the first signal of NLRP3 inflammasome activation. Meanwhile, ROS production regulated by UCP2 levels also contributed to NLRP3 inflammasome assembly and subsequent caspase 1 activation and mature IL‐1β secretion. In addition, the tlr6 knockdown rats suffering from hyperuricemia showed the lower level of IL‐1β and an ameliorative cardiac function. These findings suggest that sUA activates NLRP3 inflammasome in cardiomyocytes and they may provide one therapeutic strategy for myocardial damage induced by sUA.

Published
2020

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

Author

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

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

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

Published
2013
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4. Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8

Author

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

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

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

Published
2014

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

Author

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

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

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

Published
2013

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

Author

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

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

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

Published
2013

7. Molecular mechanisms of ATP secretion during immunogenic cell death

Author

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

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

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

Published
2013

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

Author

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

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

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

Published
2012

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

Author

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

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

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

Published
2013

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

Author

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

Subjects
*TUMOR necrosis factors, *IMMUNOGENETICS, *CANCER chemotherapy, *ANTINEOPLASTIC agents, *ANTHRACYCLINES, *DENDRITIC cells
Abstract

The antineoplastic effects of anthracyclines have been shown to rely, at least in part, on a local immune response that involves dendritic cells (DCs) and several distinct subsets of T lymphocytes. Here, we show that the administration of anthracyclines to mice bearing established neoplasms stimulates the intratumoral secretion of tumor necrosis factor α (TNFα). However, blocking the TNFα/TNF receptor (TNFR) system by three different strategies—namely, (1) neutralizing antibodies, (2) etanercept, a recombinant protein in which TNFR is fused to the constant domain of an IgG1 molecule, and (3) gene knockout—failed to negatively affect the therapeutic efficacy of anthracyclines in three distinct tumor models. In particular, TNFα-blocking strategies did not influence the antineoplastic effects of doxorubicin (a prototypic anthracycline) against MCA 205 fibrosarcomas growing in C57BL/6 mice, F244 sarcomas developing in 129/Sv hosts and H2N100 mammary carcinomas arising in BALB/c mice. These findings imply that, in contrast to other cytokines (such as interleukin-1β, interleukin-17 and interferon γ), TNFα is not required for anthracyclines to elicit therapeutic anticancer immune responses. [ABSTRACT FROM AUTHOR]

Published
2013
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11. ATP-dependent recruitment, survival and differentiation of dendritic cell precursors in the tumor bed after anticancer chemotherapy.

Author

Yuting Ma, Adjemian, Sandy, Heng Yang, Portela Catani, João Paulo, Hannani, Dalil, Martins, Isabelle, Michaud, Mickaël, Kepp, Oliver, Qader Sukkurwala, Abdul, Vacchelli, Erika, Galluzzi, Lorenzo, Zitvogel, Laurence, and Kroemer, Guido

Subjects
*ADENOSINE triphosphate, *DENDRITIC cells, *CANCER chemotherapy, *TUMOR antigens, *EXTRACELLULAR enzymes
Abstract

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

Published
2013
Full Text
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