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A crosstalk between CAR T cell subsets and the tumor microenvironment is essential for sustained cytotoxic activity

Abstract : 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.
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Submitted on : Monday, June 21, 2021 - 3:38:29 PM
Last modification on : Tuesday, October 19, 2021 - 10:29:31 PM
Long-term archiving on: : Wednesday, September 22, 2021 - 6:50:24 PM

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Morgane Boulch, Marine Cazaux, Yann Loe-Mie, Ronan Thibaut, Béatrice Corre, et al.. A crosstalk between CAR T cell subsets and the tumor microenvironment is essential for sustained cytotoxic activity. Science Immunology, American Association for the Advancement of Science, 2021, 6 (57), pp.eabd4344. ⟨10.1126/sciimmunol.abd4344⟩. ⟨pasteur-03266252⟩

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