肿瘤细胞治疗研究
英文原题：Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors.
实体瘤中的促结缔组织增生性间质对依赖内源性或过继转移 T 细胞的免疫疗法构成了严峻挑战，然而其机制尚知之甚少。
实体瘤中的促纤维增生性基质对依赖内源性或过继转移 T 细胞的免疫疗法构成巨大挑战，但其作用机制尚未得到充分了解。为阐明相关机制，本研究使用靶向成纤维细胞活化蛋白（FAP）的 CAR-T 细胞治疗已形成的促纤维增生性胰腺肿瘤；FAP 是一类癌症相关成纤维细胞（CAF）上高度过表达的酶。清除 FAP⁺ CAF 会破坏促纤维增生性基质的结构完整性，使这些高度耐药的癌症对后续靶向肿瘤抗原间皮素的 CAR-T 细胞治疗及抗 PD-1 抗体治疗产生敏感性。其机制包括克服基质依赖性 T 细胞外渗和/或血管周围浸润限制、逆转免疫排斥、解除 T 细胞抑制，以及改变免疫环境，减少髓系细胞聚集并增加内源性 CD8⁺ T 细胞和 NK 细胞浸润。这些数据有力支持将靶向肿瘤基质的疗法与靶向恶性细胞的疗法联合起来，并在临床试验中进行验证。
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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