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.