Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors

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 o...

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Bibliographic Details
Published in:Frontiers in immunology 2023-06, Vol.14, p.1175920-1175920
Main Authors: Yang, Fan, Zhang, Fan, Ji, Feng, Chen, Jiannan, Li, Jun, Chen, Zhengliang, Hu, Zhigang, Guo, Zhigang
Format: Article
Language:English
Subjects:
CAR-T cell
Humans
Immunology
immunotherapy
Immunotherapy - methods
Immunotherapy, Adoptive - methods
MSLN
Neoplasms
Receptors, Chimeric Antigen - genetics
Receptors, Chimeric Antigen - metabolism
Receptors, Immunologic - genetics
Receptors, Immunologic - metabolism
solid tumors
T-Lymphocytes
TIGIT
Tumor Microenvironment
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Summary: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-α-TIGIT for solid tumors treatment. The anti-α-TIGIT effectively enhanced the efficacy of anti-MLSN CAR-T cells on the killing of target cells . 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 . 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.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2023.1175920