TIGIT blockade increases efficacy of PD-1 blockade combined with radiation therapy in triple-negative breast cancer model.

Abstract

T-cell immunoreceptor with Ig and ITIM domains (TIGIT) suppresses functions of CD8⁺ T cells, and radiation therapy (RT) induces stimulation of regulatory T cells (Tregs), thereby limiting antitumor efficacy. This study aims to investigate the role of TIGIT in the immunosuppressive tumor environment and evaluate the potential of TIGIT blockade (αTIGIT) to enhance antitumor immune responses. We analyzed public transcriptomic data to identify the expression patterns of TIGIT on T cells in breast cancer and its prognostic impact. In addition, a murine TNBC model was utilized to evaluate the effects of αPD-1, local RT, and αTIGIT. T cells in tumors, tumor-draining lymph nodes (TdLNs), and the spleen were analyzed to assess the antitumor immune responses upon the treatments. The analysis revealed that TIGIT is predominantly expressed on T cells within breast cancer, and the expression of TIGIT was associated with poor outcomes in TNBC patients. In the murine model, the combination of αPD-1 and RT increased TIGIT⁺CD226⁺CD8⁺ TILs, which are crucial for the efficacy of αTIGIT. Adding αTIGIT to αPD-1 and RT (αPD-1/RT) resulted in a synergistic antitumor effect, which was accompanied by increased infiltration of CD8⁺ TILs in both irradiated and nonirradiated tumors by the triple combination therapy compared to αPD-1/RT. The triple combination therapy also resulted in a less exhausted phenotype among CD8⁺ TILs and increased the proliferation of splenic CD8⁺ T cells. Moreover, αTIGIT significantly reduced Tregs in tumors, TdLNs, and the spleen when combined with αPD-1/RT. αTIGIT exhibits synergistic effects when added to αPD-1/RT by increasing the infiltration and activation of CD8⁺ TILs while reducing Tregs. The study suggests that αTIGIT could be an effective strategy to enhance the antitumor efficacy of αPD-1 and RT in TNBC.