Xiao et al. studied whether desmoplastic stroma in the TME shield solid tumors from T-cell immunotherapies. Treatment of mice bearing pancreatic tumors with CAR T cells targeting FAP, highly expressed on CAFs, depleted desmoplastic matrices, rendering tumors susceptible to treatment with mesothelin-targeted CAR T cells. In addition, while anti-PD-1 alone was ineffective, FAP-CAR T cell effects were potentiated by subsequent PD-1 blockade. Intratumorally, FAP-CAR T cell treatment decreased TAM and CD4+Foxp3+ Treg cell levels, increased cDC1s, and enhanced infiltration of endogenous CD8+ T and NK cells, with increased tumoricidal activity into tumor nests.
Contributed by Katherine Turner
ABSTRACT: The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the mechanisms are poorly understood. To define mechanisms involved, here we treat established desmoplastic pancreatic tumors with CAR T cells directed to fibroblast activation protein (FAP), an enzyme highly overexpressed on a subset of cancer-associated fibroblasts (CAFs). Depletion of FAP(+) CAFs results in loss of the structural integrity of desmoplastic matrix. This renders these highly treatment-resistant cancers susceptible to subsequent treatment with a tumor antigen (mesothelin)-targeted CAR T cells and to anti-PD-1 antibody therapy. Mechanisms include overcoming stroma-dependent restriction of T cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving T cell suppression, and altering the immune landscape by reducing myeloid cell accumulation and increasing endogenous CD8(+) T cell and NK cell infiltration. These data provide strong rationale for combining tumor stroma- and malignant cell-targeted therapies to be tested in clinical trials.
Author Info: (1) Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. (2) Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA
Author Info: (1) Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. (2) Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. (3) Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. (4) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. (5) Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. (6) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. (7) Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. (8) Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. (9) Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. (10) Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. (11) Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. (12) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. (13) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. (14) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (15) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. (16) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. (17) Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. epure@upenn.edu.
