Abstract 1360: TIGIT blockade combined with local radiotherapy and PD-1 blockade in a murine triple-negative breast cancer model

Abstract

Abstract Background: Immune checkpoint blockades (ICB) improve outcomes of patients with some solid tumors such has melanoma and lung cancer, however the efficacy of ICB alone showed limited efficacy in many other tumors such as breast cancer. Radiation therapy is a promising combination partner of ICB as a strong immune stimulator so called in situ tumor vaccine, however it also can increase immune suppressive repertoires. TIGIT (T cell Immunoglobulin and ITIM domain) is an inhibitory receptor expressed on activated T cells and NK cells. We evaluated the effects of TIGIT blockade in addition to local RT and PD-1 blockade as a strategy to overcome therapeutic resistance of ICI in a murine breast cancer model. Materials and Methods: 4T1-Luc tumors were treated with various strategies including control, RT, anti-PD-1, anti-TIGIT, RT+anti-PD-1, RT+anti-TIGIT, anti-PD-1+anti-TIGIT, and RT+anti-PD-1+anti-TIGIT. A total of 24 Gy in 3 fractions at 1 week was delivered to the tumor at hindlimb (primary tumor) while the tumor at flank (secondary tumor) was left unirradiated. 10 mg/kg of anti-PD-1 blocking antibodies and 10 mg/kg of anti-TIGIT blocking antibodies were intraperitoneally injected for 6 times for 2 weeks. Flow cytometry, IHC staining, and ELISA were performed to assess the immunologic status after treatments. Results: The triple combination therapy (TCT) group showed the most superior growth delay of primary and secondary tumor growth among treatments. The number of metastatic lung nodule was significantly reduced by TCT as well. Plasma levels of interferon-β and interferon-γ were the highest after TCT. Moreover, TCT significantly increased the proportion of splenic CD8+ dendritic cells among myeloid cells, and effector-memory (CD44+CD62L−) cells among splenic Foxp3− non-regulatory CD4+ and CD8+ T cells. Furthermore, expression of CD226, which is an activating counter-receptor of TIGIT, on splenic CD8+ T cells was elevated by TIGIT blockade, possibly suggesting the activation of systemic immune response by addition of TIGIT blockade to local RT and PD-1 blockade. Meanwhile, TCT decreased splenic Foxp3+ regulatory T cells, as well as the expression of CD39 on splenic Foxp3+ regulatory T cells. The increase of CD8+ T cell infiltration in primary and secondary tumors was most prominent in TCT group. Conclusion: TIGIT blockade elicits systemic immune responses in a murine triple-negative breast cancer model. when combined with local RT and PD-1 blockade, which were correlated with significant delay in the growth of both irradiated and unirradiated tumors. These results suggest that TIGIT blockade could be a viable approach to increase the efficacy of RT and immune checkpoint inhibitors in breast cancer which is a relatively immunologically cold tumor. (Work supported by a grant from National Research Foundation of Korea #2023R1A2C3003782 to In Ah Kim). Citation Format: Seongmin Kim, Seung Hyuck Jeon, In Ah Kim. TIGIT blockade combined with local radiotherapy and PD-1 blockade in a murine triple-negative breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1360.