Abstract 2167: AKT inhibition enhances antitumor efficacy of radiation and immune checkpoint blockade in triple-negative breast cancer by modulating tumor-infiltrating myeloid cells

Abstract Although radiotherapy (RT) and immune checkpoint blockade (ICB) are effective for treatment of triple-negative breast cancer (TNBC), significant portion of patients do not experience a clinical benefit, partly due to activation of immunosuppressive cells. Capivasertib, an AKT inhibitor, is approved for use in advanced luminal breast cancer, but its immunomodulatory role in breast cancer remains still unclear. Given the ability of PI3K/AKT/mTOR inhibition to regulate immunosuppressive myeloid cells, we hypothesized that capivasertib could enhance the efficacy of RT and ICB in TNBC. In this study, we investigated the antitumor effects and phenotypes of immune cells in 4T1 syngeneic mouse TNBC model treated with RT, dual ICB (PD-L1 and CTLA-4 blockade), and capivasertib. A dual-tumor model was used to examine abscopal effects, with one tumor receiving RT and the other remaining unirradiated. We found that the quadruple therapy (i.e. RT + anti-PD-L1 + anti-CTLA-4 + capivasertib) resulted in greatest growth delay of both irradiated (primary) and unirradiated (secondary) tumors, along with the lowest number of metastatic lung nodules. Notably, compared to the RT + anti-PD-L1 + anti-CTLA-4 treatment, the quadruple therapy significantly reduced tumor-infiltrating macrophages, with an increase in inflammatory M1 macrophages and a decrease in immunosuppressive M2 macrophages. Moreover, CD86+ mature dendritic cells within tumor microenvironment were increased by addition of capivasertib to RT + anti-PD-L1 + anti-CTLA-4 treatment. These changes were not observed within the spleen and tumor-draining lymph node. Proportion and phenotypes of myeloid-derived suppressor cells (MDSCs) and T cells in tumor were not significantly changed by the quadruple therapy. These findings suggest that capivasertib, when combined with RT and ICB, led to less immunosuppressive tumor microenvironment by modulating tumor-infiltrating myeloid cells. Taken together, this combination strategy could be a viable approach to overcome therapeutic resistance of ICB in TNBC patients. (Work supported by grants from KHIDI & AstraZeneca, and the National Research Foundation of Korea #2023R1A2C3003782) Citation Format: Nawon Park, Seung Hyuck Jeon, Yoomin Kim, Seongmin Kim, In Ah Kim. AKT inhibition enhances antitumor efficacy of radiation and immune checkpoint blockade in triple-negative breast cancer by modulating tumor-infiltrating myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2167.