A crosstalk between CAR T cell subsets and the tumor microenvironment is essential for sustained cytotoxic activity
| Autor: | Yann Loe-Mie, Philippe Bousso, Marine Cazaux, Zacarias Garcia, Fabrice Lemaître, Béatrice Corre, Capucine L. Grandjean, Ronan Thibaut, Morgane Boulch |
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| Přispěvatelé: | Dynamiques des Réponses immunes - Dynamics of Immune Responses, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The work was supported by Institut Pasteur,Inserm and an Advanced grant (ENLIGHTEN) from the European Research Council (P.B). M. Cazaux received financial support from ITMO Cancer ‘Alliance Nationale pour les Sciences de la Vie et de la Santé’ within the framework of the Cancer Plan., European Project: 741167,ERC-2016-ADG,ENLIGHTEN(2018), HUGOT, Bérengère, INTEGRATION AND PROPAGATION OF IMMUNOLOGICAL SIGNALS DURING CANCER AND INFECTION - ENLIGHTEN - 2018-01-01 - 2022-12-31 - 741167 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Lymphoma
B-Cell T cell [SDV]Life Sciences [q-bio] Antigens CD19 Immunology Receptors Antigen T-Cell Cell Communication Biology Lymphocyte Activation Immunotherapy Adoptive Interferon-gamma Mice 03 medical and health sciences 0302 clinical medicine Immune system Antigen Antigens Neoplasm T-Lymphocyte Subsets Cell Line Tumor Neoplasms Tumor Microenvironment medicine Animals Humans Cytotoxic T cell Cytotoxicity 030304 developmental biology 0303 health sciences Tumor microenvironment Receptors Chimeric Antigen Gene Expression Profiling Computational Biology General Medicine Cytotoxicity Tests Immunologic Chimeric antigen receptor [SDV] Life Sciences [q-bio] Disease Models Animal medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Cytokines human activities CD8 |
| Zdroj: | Science Immunology Science Immunology, 2021, 6 (57), pp.eabd4344. ⟨10.1126/sciimmunol.abd4344⟩ Science Immunology, American Association for the Advancement of Science, 2021, 6 (57), pp.eabd4344. ⟨10.1126/sciimmunol.abd4344⟩ |
| ISSN: | 2470-9468 |
| DOI: | 10.1126/sciimmunol.abd4344⟩ |
| Popis: | International audience; Chimeric antigen receptor (CAR) T cell therapy relies on the activity of a large pool of tumor-targeting cytotoxic effectors. Whether CAR T cells act autonomously or require interactions with the tumor microenvironment (TME) remains incompletely understood. Here, we report an essential cross-talk between CAR T cell subsets and the TME for tumor control in an immunocompetent mouse B cell lymphoma model of anti-CD19 CAR T cell therapy. Using single-cell RNA sequencing, we revealed substantial modification of the TME during CAR T cell therapy. Interferon-γ (IFN-γ) produced by CAR T cells not only enhanced endogenous T and natural killer cell activity but was also essential for sustaining CAR T cell cytotoxicity, as revealed by intravital imaging. CAR T cell-derived IFN-γ facilitated host interleukin-12 production that supported host immune and CAR T cell responses. Compared with CD8+ CAR T cells, CD4+ CAR T cells were more efficient at host immune activation but less capable of direct tumor killing. In summary, CAR T cells do not act independently in vivo but rely instead on cytokine-mediated cross-talk with the TME for optimal activity. Invigorating CAR T cell interplay with the host represents an attractive strategy to prevent relapses after therapy. |
| Databáze: | OpenAIRE |
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