Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors
Zebin Xiao, Leslie Todd, Li Huang, Estela Noguera-Ortega, Zhen Lu, Lili Huang, Meghan C. Kopp, Yue Li, Nimisha B. Pattada, Wenqun Zhong, Wei Guo, John Scholler, Maria Liousia, Charles‐Antoine Assenmacher, Carl H. June, Steven Μ. Albelda, Ellen Puré
Abstract
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.