嵌合抗原受体（CAR）T细胞免疫疗法在治疗血液恶性肿瘤方面已取得成功；然而，其在实体瘤中的功效和应用仍然有限。免疫抑制因子，特别是抑制性检查点分子，限制实体瘤内 CAR T 细胞的活性。检查点通路的调节已成为促进 CAR T 细胞抗肿瘤反应的一种有前景的方法。程序性细胞死亡蛋白 1 (PD1) 和具有 Ig 和 ITIM 结构域的 T 细胞免疫受体 (TIGIT) 是抑制 T 细胞抗肿瘤活性的两种关键免疫检查点分子。同时靶向这两种抑制分子可能是一种有效的检查点调节策略。在这里，我们开发了一种PD1-TIGIT嵌合免疫检查点转换受体（CISR），它通过逆转PD1/PDL1和/或TIGIT/CD155的抑制性检查点信号来增强CAR T细胞免疫疗法的功效。除了中和 PDL1 和 CD155 之外，这种嵌合受体还设计有 CD28 的跨膜区和胞内结构域，从而有效增强 T 细胞存活和肿瘤靶向功能。值得注意的是，在PDL1和CD155的同时刺激下，与传统的CAR T细胞相比，CISR-CAR T细胞在体外的细胞存活、增殖、细胞因子释放和细胞毒性方面表现出优越的性能。利用细胞系和患者来源的异种移植肿瘤模型进行的实验表明，CISR-CAR T 细胞在体内表现出强大的浸润和抗肿瘤效率。我们的结果凸显了 CISR 策略增强 T 细胞抗肿瘤功效的潜力，并为基于 T 细胞的免疫疗法提供了替代方法。© 2023 作者。经泰勒许可出版

Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated success in the treatment of hematological malignancies; however, its efficacy and applications in solid tumors remain limited. Immunosuppressive factors, particularly inhibitory checkpoint molecules, restrict CAR T cell activity inside solid tumors. The modulation of checkpoint pathways has emerged as a promising approach to promote anti-tumor responses in CAR T cells. Programmed cell death protein 1 (PD1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are two critical immune-checkpoint molecules that suppress anti-tumor activity in T cells. Simultaneous targeting of these two inhibitory molecules could be an efficient checkpoint modulation strategy. Here, we developed a PD1-TIGIT chimeric immune-checkpoint switch receptor (CISR) that enhances the efficacy of CAR T cell immunotherapy by reversing the inhibitory checkpoint signals of PD1/PDL1 and/or TIGIT/CD155. In addition to neutralizing PDL1 and CD155, this chimeric receptor is engineered with the transmembrane region and intracellular domain of CD28, thereby effectively enhancing T cell survival and tumor-targeting functions. Notably, under simultaneous stimulation of PDL1 and CD155, CISR-CAR T cells demonstrate superior performance in terms of cell survival, proliferation, cytokine release, and cytotoxicity in vitro, compared with conventional CAR T cells. Experiments utilizing both cell line- and patient-derived xenotransplantation tumor models showed that CISR-CAR T cells exhibit robust infiltration and anti-tumor efficiency in vivo. Our results highlight the potential for the CISR strategy to enhance T cell anti-tumor efficacy and provide an alternative approach for T cell-based immunotherapies.© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.