嵌合抗原受体（CAR）T细胞已经改变了血液系统恶性肿瘤的治疗格局。然而，由于肿瘤微环境（TME）的免疫抑制性质导致T细胞浸润不足，CAR T细胞对实体肿瘤的效果较差。在本研究中，我们评估了对前列腺癌患者来源的移植物模型中，针对Lewis Y抗原（LeY）的特异性CAR T细胞的疗效。在体外实验中，LeY CAR T细胞可以直接杀死源自雄激素受体（AR）阳性或AR缺失的移植物器官样结构。而在体内实验中，虽然LeY CAR T细胞单独不能减少肿瘤生长，但是给予一次卡铂的剂量可降低肿瘤负担。卡铂对TME具有促炎作用，促进了早期和持久的CAR T细胞浸润，包括改变了癌相关成纤维细胞的表型、增强了细胞外基质降解和转向M1型巨噬细胞分化。在对卡铂不敏感的移植物模型中，CAR T细胞的浸润被抑制，然而观察到了肿瘤负担的减少和T细胞活化的增加。这些结果表明，卡铂可以提高CAR T细胞治疗的疗效，反应程度取决于TME中诱导的变化。©2023 Springer Nature Limited.

Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (LeY)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, LeY CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although LeY CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.© 2023. Springer Nature Limited.