自递送 TIGIT 阻断 scFv 增强实体瘤中的 CAR-T 免疫治疗

Chimeric antigen receptor T cell therapy has become an important immunotherapeutic tool for overcoming cancers.

However, the efficacy of CAR-T cell therapy in solid tumors is relatively poor due to the complexity of the tumor microenvironment and inhibitory immune checkpoints. TIGIT on the surface of T cells acts as an immune checkpoint by binding to CD155 on the tumor cells' surface, thereby inhibiting tumor cell killing.

Blocking TIGIT/CD155 interactions is a promising approach in cancer immunotherapy. In this study, we generated anti-MLSN CAR-T cells in combination with anti- -TIGIT for solid tumors treatment. The anti- -TIGIT effectively enhanced the efficacy of anti-MLSN CAR-T cells on the killing of target cells in vitro .

In addition, we genetically engineered anti-MSLN CAR-T cells with the capacity to constitutively produce TIGIT-blocking single-chain variable fragments.

Our study demonstrated that blocking TIGIT significantly promoted cytokine release to augment the tumor-killing effect of MT CAR-T cells.

Moreover, the self-delivery of TIGIT-blocking scFvs enhanced the infiltration and activation of MT CAR-T cells in the tumor microenvironments to achieve better tumor regression in vivo . These results suggest that blocking TIGIT effectively enhances the anti-tumor effect of CAR-T cells and suggest a promising strategy of combining CAR-T with immune checkpoints blockade in the treatment of solid tumors.