CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy

Alba Rodriguez-Garcia, Rachel C. Lynn, Mathilde Poussin, Monika A. Eiva, Lauren C. Shaw, Roddy S. O’Connor, Nicholas G. Minutolo, Victoria Casado-Medrano, Gonzalo Lopez, Takami Matsuyama and Daniel J. Powell ()
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Alba Rodriguez-Garcia: University of Pennsylvania
Rachel C. Lynn: University of Pennsylvania
Mathilde Poussin: University of Pennsylvania
Monika A. Eiva: University of Pennsylvania
Lauren C. Shaw: University of Pennsylvania
Roddy S. O’Connor: University of Pennsylvania
Nicholas G. Minutolo: University of Pennsylvania
Victoria Casado-Medrano: University of Pennsylvania
Gonzalo Lopez: Icahn School of Medicine at Mount Sinai
Takami Matsuyama: Kagoshima University
Daniel J. Powell: University of Pennsylvania

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Here, we demonstrate that a subset of TAMs that express folate receptor β (FRβ) possess an immunosuppressive M2-like profile. In syngeneic tumor mouse models, chimeric antigen receptor (CAR)-T cell-mediated selective elimination of FRβ+ TAMs in the TME results in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8+ T cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR-T cells also improves the effectiveness of tumor-directed anti-mesothelin CAR-T cells, while simultaneous co-administration of both CAR products does not. These results highlight the pro-tumor role of FRβ+ TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens.

Date: 2021
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DOI: 10.1038/s41467-021-20893-2

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