Rodriguez-Garcia et al. investigated the roles of tumor-associated macrophages (TAMs) in the TME of an ovarian cancer model. TAMs expressing folate receptor β (FRβ) exhibited an immunosuppressive M2-like profile. Selective depletion of FRβ+ TAMs with FRβ-CAR T cells in syngeneic tumor models delayed tumor growth and improved survival, with increased levels of inflammatory monocytes, neutrophils, and tumor-specific CD8+ T cells in blood and ascites. Treatment with FRβ CAR-T cells prior to treatment with antitumor (Mesothelin) CAR-T cells improved tumor-specific CAR T cell efficacy, whereas simultaneous delivery showed no improvement.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Pathology and Laboratory Medicine, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cell
Author Info: (1) Department of Pathology and Laboratory Medicine, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Pathology and Laboratory Medicine, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Pathology and Laboratory Medicine, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (4) Department of Pathology and Laboratory Medicine, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (5) Department of Pathology and Laboratory Medicine, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (6) Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (7) Department of Pathology and Laboratory Medicine, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (8) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (9) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) The Center for Advanced Biomedical Sciences and Swine Research, Kagoshima University, Kagoshima, Japan. (11) Department of Pathology and Laboratory Medicine, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. poda@pennmedicine.upenn.edu. Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. poda@pennmedicine.upenn.edu.
