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Abstract
Background and purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

치료군별 종양 성장을 비교했을 때, RT를 받은 primary tumor 및 받지 않은 secondary tumor 모두에서 삼중병용치료(αPD-1+RT+α-TIGIT)를 했을 때 α-PD-1+RT보다 더욱 현저한 종양 성장 억제 효과가 관찰되었습니다. (a: primary tumor, b: secondary tumor).

PD-1 blockade와 RT의 병용치료에 TIGIT blockade를 추가하였을 때 CD8⁺ TIL의 tumor infiltration이 증가하고 CD4⁺ T cell 내 Treg의 비율이 감소하였습니다.

Affiliations

Seongmin Kim 1, Seung Hyuck Jeon 2, Yoomin Kim 3, Nawon Park 3, In Ah Kim 4
1Department of Tumor Biology and Cancer Research Institute, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea; Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
2Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
3Department of Tumor Biology and Cancer Research Institute, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
4Department of Tumor Biology and Cancer Research Institute, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea; Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: inah228@snu.ac.kr.