Enhancing T cell anti-tumor efficacy with a PD1-TIGIT chimeric immune-checkpoint switch receptor

ABSTRACT

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.

KEYWORDS:

• Cancer immunotherapy
• chimeric antigen receptor T
• immune-checkpoint
• PD1
• TIGIT

Acknowledgments

We thank Chunping Lv, Dan Zhao, Zhongqing Lin, Shen Zheng, and Lisha Ma for technical assistance. We thank Dr. Weifeng Lai and Dr. Huangfan Xie for critical review of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

JZ, JD, and CD designed the research, performed the experiments, analyzed the data, and wrote the manuscript. SS wrote the manuscript. QZ and HL assisted with some experiments and provided technical assistance. YB and HD designed the research, supervised the research, and wrote the manuscript.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2265703

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [32288102, 32071413 and 82072576].