Wang Xi, Lai Zhiheng, Pang Yanyang, Sun Qinghui, Yang Wenli, Wang Wu
Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Tropical Medicine Medicine, Hainan Medical University, Haikou, 570100, China.
Department of Anesthesiology, Haikou Third People's Hospital, Haikou, 570100, China.
Heliyon. 2023 Jan 3;9(1):e12688. doi: 10.1016/j.heliyon.2022.e12688. eCollection 2023 Jan.
CD105 has become a promising target of immunotherapy development for highly specific expression on the neovascular surface of most types of tumor cells. In previous studies, we constructed a CAR T cell (CD105 CAR T cell) and observed significant antitumor activity. In this study, we optimized the structure of CD105 CAR to increase PD-1 antibody secretion function (CD105 × PD-1 CAR T cells).
we tested whether Increased PD-1 antibody secretion with CAR T cells targeted CD105 could promote in vitro proliferation, proinflammatory cytokine production and cytotoxicity,or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy.
Our data showed that the PD-1 antibody secreted by CD105 × PD-1 CAR T cells could specifically bind to the PD-1 receptor of T cells then blocked the PD-1/PD-L-1 signaling pathway, thus enhancing the activation and proliferation of CAR T cells. After incubation of CD105 × PD-1 CAR T cells with HepG2 as a hepatocellular carcinoma cell line expressing CD105, the results showed that CD105 × PD-1 CAR T cells increased the expression levels of CD69 and CD62L, enhanced the proliferation capacity of CAR T cells, and secreted more IL-2, TNF-α and IFN-γ than CD105 CAR T cells.
These data showed that CD105 × PD-1 CAR T cells was specifically killing tumor cells in vitro and in vivo. Our findings may therefore provide a promising new strategy for the improvement of CAR T therapy for solid tumors.
CD105因其在大多数类型肿瘤细胞的新生血管表面高度特异性表达，已成为免疫治疗开发中一个有前景的靶点。在先前的研究中，我们构建了一种嵌合抗原受体T细胞（CD105嵌合抗原受体T细胞），并观察到显著的抗肿瘤活性。在本研究中，我们优化了CD105嵌合抗原受体的结构，以增加PD-1抗体分泌功能（CD105×PD-1嵌合抗原受体T细胞）。
我们测试了靶向CD105的嵌合抗原受体T细胞增加PD-1抗体分泌是否能促进体外增殖、促炎细胞因子产生和细胞毒性。对于体内实验，我们构建了皮下移植肿瘤模型，并将其植入NOD/SCID小鼠体内，以验证该疗法的抗肿瘤效果。
我们的数据表明，CD105×PD-1嵌合抗原受体T细胞分泌的PD-1抗体可以特异性结合T细胞的PD-1受体，进而阻断PD-1/PD-L-1信号通路，从而增强嵌合抗原受体T细胞的激活和增殖。用表达CD105的肝癌细胞系HepG2与CD105×PD-1嵌合抗原受体T细胞孵育后，结果显示，CD105×PD-1嵌合抗原受体T细胞增加了CD69和CD62L的表达水平，增强了嵌合抗原受体T细胞的增殖能力，并且比CD105嵌合抗原受体T细胞分泌更多的白细胞介素-2、肿瘤坏死因子-α和干扰素-γ。
这些数据表明，CD105×PD-1嵌合抗原受体T细胞在体外和体内均能特异性杀伤肿瘤细胞。因此，我们的研究结果可能为改善实体瘤的嵌合抗原受体T细胞疗法提供一种有前景的新策略。
