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Article Dans Une Revue Nature Cancer Année : 2023

Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity

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Abstract CD4 + T cells and CD4 + chimeric antigen receptor (CAR) T cells display highly variable antitumor activity in preclinical models and in patients; however, the mechanisms dictating how and when CD4 + T cells promote tumor regression are incompletely understood. With the help of functional intravital imaging, we report that interferon (IFN)-γ production but not perforin-mediated cytotoxicity was the dominant mechanism for tumor elimination by anti-CD19 CD4 + CAR T cells. Mechanistically, mouse or human CD4 + CAR T-cell-derived IFN-γ diffused extensively to act on tumor cells at distance selectively killing tumors sensitive to cytokine-induced apoptosis, including antigen-negative variants. In anti-CD19 CAR T-cell-treated patients exhibiting elevated CAR CD4:CD8 ratios, strong induction of serum IFN-γ was associated with increased survival. We propose that the sensitivity of tumor cells to the pro-apoptotic activity of IFN-γ is a major determinant of CD4 + CAR T-cell efficacy and may be considered to guide the use of CD4 + T cells during immunotherapy.
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pasteur-04158305 , version 1 (11-07-2023)

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Morgane Boulch, Marine Cazaux, Alexis Cuffel, Marion Guerin, Zacarias Garcia, et al.. Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity. Nature Cancer, 2023, ⟨10.1038/s43018-023-00570-7⟩. ⟨pasteur-04158305⟩
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