基质
癌症研究
免疫系统
间质细胞
外渗
成纤维细胞活化蛋白
T细胞
肿瘤微环境
免疫疗法
生物
免疫抑制
免疫学
医学
癌症
免疫组织化学
遗传学
作者
Zhang Xiao,Leslie Todd,Huang Li,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
标识
DOI:10.1038/s41467-023-40850-5
摘要
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.
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