孤核受体NR2F6对靶向磷脂酰肌醇蛋白聚糖-3的CAR-T细胞抗肝癌疗效的影响及机制研究

Chimeric antigen receptor modified T (CAR-T)-cell therapy has been successfully applied to the treatment of hematologic malignancies, but still faces many challenges in solid tumors. Our research team previously had carried out the first clinical trials of hepatocellular carcinoma (HCC) in the world wide. In this phase I study, although the GPC3 CAR-T cell immunotherapy showed good safety and partial effectiveness, but the efficacy remains to be further improved. This may be due to the hostile tumor microenvironment inhibits CAR-T survive and antitumor activity in solid tumor. It is recently reported that orphan nuclear receptor NR2F6 appeared to be an intracellular immune checkpoint, directly suppressing the activation of T cells and might be served as a potential cancer therapeutic target. Currently, there were no relevant studies about the roles of NR2F6 on CAR-T cell therapy for solid tumors. Therefore, in this study, we aim to gain insights into two issues: 1) NR2F6 on the antitumor efficacy of CAR-T cell therapy and the underlying molecular mechanisms; 2) Whether the blockade of NR2F6 immunosuppression could boost CAR-T cell therapy as well as the underlying molecular mechanisms. We believe that the elucidation of these two issues shell help us understand the immune escape mechanisms of tumor cells against CAR-T cells and may also provide a kind of new potential strategy for cancer immunotherapy.

嵌合抗原受体修饰T细胞(CAR-T)疗法在血液系统恶性肿瘤中已取得巨大成功，然而CAR-T对实体肿瘤的治疗仍面临诸多挑战。申请者所在研究团队前期开展了全球首个肝细胞癌的临床试验，尽管I期临床试验GPC3 CAR-T 显示出了良好的安全性和一定的有效性，但治疗效果仍有待进一步提高，这可能是由于肿瘤复杂的免疫微环境抑制了CAR-T的存活以及对肿瘤组织的免疫杀伤。据最新文献报道，孤核受体NR2F6具有抑制T细胞活化的功能，被认为是T细胞内的免疫检查点，有望成为肿瘤治疗的重要靶标。目前，尚未有报道NR2F6在CAR-T抗肿瘤疗效中的作用。因此，本研究旨在探讨两方面的内容：1. NR2F6在CAR-T抗肿瘤疗效中的作用及机制；2. NR2F6进行干预后是否能够增强CAR-T的疗效及具体作用机理。该课题的研究不仅将有助于我们理解肿瘤细胞对CAR-T的免疫逃逸机制，也将有望为肝癌治疗提供一种新的策略。

嵌合抗原受体修饰T淋巴细胞(CAR-T)疗法在血液系统恶性肿瘤中已取得了突破性进展，然而，CAR-T在实体瘤治疗中仍面临巨大挑战，其主要原因是由于实体肿瘤存在的异质性以及肿瘤抑制性免疫微环境抑制了CAR-T的存活以及免疫杀伤活性。本课题主要研究了NFAT调控表达的细胞因子IL-12以及IL-18对GPC3-CAR-T细胞抗肝癌疗效的影响及机制研究，并进一步探讨了CAR-T细胞联合多激酶抑制剂索拉非尼在肝细胞癌中的疗效及机理。本研究结果显示，在免疫完善以及免疫缺陷的小鼠模型中，NFAT诱导调控表达的IL-12或IL-18细胞因子能够显著增强CAR-T细胞的抗肿瘤疗效，且几乎不会产生明显毒副作用。CAR-T细胞与小分子抑制剂索拉非尼联合用药的结果表明，索拉非尼可增强GPC3-CAR T细胞的抗肝细胞癌活性，其中部分机制是通过促进肿瘤相关巨噬细胞中IL-12的分泌。本研究将为肝癌临床治疗提供一种新的治疗策略和思路。亦将有望索拉非尼与GPC3-CAR T细胞的临床联合治疗肝癌提供了重要的实验及理论依据。