Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors

作者：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 · 发表于：Nature Communications · 年份：2023 · DOI：10.1038/s41467-023-40850-5 · 被引用次数：262 · 研究领域：CAR-T cell therapy research、Pancreatic and Hepatic Oncology Research、Cancer Immunotherapy and Biomarkers

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.