Research ArticleIMMUNOTHERAPY

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

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Science Immunology  26 Mar 2021:
Vol. 6, Issue 57, eabd4344
DOI: 10.1126/sciimmunol.abd4344

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CAR T cells collaborate to fight tumors

Chimeric antigen receptor (CAR) T cells have achieved clinical success in treating B cell malignancies. Boulch et al. used intravital microscopy to visualize in situ interactions between tumors and anti-CD19 CD4+ or CD8+ CAR T cells and single-cell transcriptomics to examine subsequent changes to the tumor microenvironment in an immunocompetent mouse model of B cell lymphoma. While CD4+ CAR T cells were more effective at stimulating host immune responses, CD8+ CAR T cells excelled at direct tumor cell killing, both of which required CAR T cell–intrinsic IFN-γ expression. Host sensing of IFN-γ and IL-12 production were also required for CAR T cell function, supporting that cross-talk between CAR T cells and the tumor microenvironment is necessary for optimal CAR T cell efficacy against tumors.

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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