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.

实体瘤中的促纤维增生基质对依赖内源性或过继转移 T 细胞的免疫疗法提出了巨大的挑战，然而，其机制仍知之甚少。为了定义所涉及的机制，在这里，我们用针对成纤维细胞激活蛋白（FAP）的 CAR T 细胞治疗已形成的促纤维增生性胰腺肿瘤，FAP 是一种在癌症相关成纤维细胞（CAF）子集上高度过表达的酶。 FAP ⁺ CAF 的消耗导致促纤维基质结构完整性的丧失。这使得这些高度耐药的癌症很容易受到针对肿瘤抗原（间皮素）的 CAR T 细胞的后续治疗和抗 PD-1 抗体疗法的影响。机制包括克服基质依赖性 T 细胞外渗和/或血管周围侵袭的限制、逆转免疫排斥、缓解 T 细胞抑制以及通过减少骨髓细胞积累和增加内源性 CD8 ⁺ T 细胞和 NK 细胞浸润来改变免疫景观。这些数据为结合肿瘤基质和恶性细胞靶向疗法在临床试验中进行测试提供了强有力的理由。