Chimeric antigen receptor-engineered T cells (CAR Ts) targeting CD19 have shown unprecedented prognosis in treating hematological cancers. However, the lack of a tumor-specific antigen as the target and an inhospitable tumor environment limit the clinical application of CAR T in solid tumors. Tumor-infiltrating T lymphocytes (TIL) exhibit diverse T cell receptor clonality and superior tumor-homing abilities. Therefore, in our study, human CD19-target TIL CAR-Ts armed with CD3ζ and 4-1BB signaling domains were constructed. Mouse colorectal cancer CT26 cells expressing human CD19 (hCD19+-CT26) were developed to assess the anti-tumor activity of TIL CAR-T cells, both in vitro and in vivo. Compared with splenic CAR T adoptive transfer, TIL CAR-T administration showed superior tumor suppression ability in hCD19+-CT26 tumor-bearing mice. Furthermore, more T cells were found at the tumor site and had lower exhaustion-related inhibitory receptor (T cell immunoglobulin and mucin domain-containing protein 3, Tim3) expression and higher immune memory molecule (CD62L) expression. Overall, we provided an artificial tumor-specific antigen in solid tumors and demonstrated that combined CAR-expressing TIL-Ts (TIL CAR-Ts) exhibited strong anti-tumor activity, with improved T cell infiltration and immune memory. Our humanized tumor antigen presented platform of mice suggests that TIL CAR-T-based adoptive therapy could be a promising strategy for solid cancer treatment.
靶向CD19的嵌合抗原受体T细胞（CAR T）在治疗血液系统恶性肿瘤方面展现出前所未有的疗效。然而，由于缺乏肿瘤特异性抗原靶点及肿瘤微环境的免疫抑制特性，CAR T在实体瘤中的临床应用受到限制。肿瘤浸润性T淋巴细胞（TIL）具有多样化的T细胞受体克隆性及优异的肿瘤归巢能力。因此，本研究构建了携带CD3ζ与4-1BB信号结构域、靶向人CD19的TIL CAR-T细胞。通过建立表达人CD19的小鼠结直肠癌CT26细胞系（hCD19+-CT26），在体外和体内评估TIL CAR-T细胞的抗肿瘤活性。与脾源性CAR T过继转移相比，TIL CAR-T细胞在hCD19+-CT26荷瘤小鼠模型中表现出更强的肿瘤抑制能力。进一步分析显示，肿瘤部位浸润的T细胞数量更多，其耗竭相关抑制性受体（T细胞免疫球蛋白黏蛋白分子3，Tim3）表达较低，而免疫记忆分子（CD62L）表达较高。本研究通过在实体瘤中构建人工肿瘤特异性抗原模型，证明表达CAR的TIL-T细胞（TIL CAR-T）具有更强的抗肿瘤活性，同时能改善T细胞浸润并增强免疫记忆功能。我们建立的人源化肿瘤抗原小鼠平台表明，基于TIL CAR-T的过继细胞疗法可能成为实体瘤治疗的一种有前景的策略。
肿瘤(癌症)患者之家