Abstract B073: MOMP-dependent cytotoxicity and immunogenicity of radiation therapy in breast cancer

Abstract In 2023, an estimated 297,790 new cases of invasive breast cancer (BC) have been diagnosed to women in the US, causing an estimated 55,720 deaths, most of which originated from hormone receptor (HR+) BC. In this sense, radiation therapy (RT) has attracted attention as a potential tool to convert HR+ BCs that are scarcely infiltrated by immune cells (so-called ‘cold’) into highly infiltrated (so-called ‘hot’) immune checkpoint blockers (ICB)-responsive tumors thanks, among other factors, to the release of damage-associated molecular patterns (DAMPs), which promote the recognition of cancer cell death as immunogenic. In line with this notion, RT has been shown to positively interact with ICBs in preclinical models of mammary carcinoma, melanoma, glioma and glioblastoma, among others. Mitochondrial outer membrane permeabilization (MOMP) as mediated by BCL2 associated X, apoptosis regulator (BAX) and BCL2 antagonist/killer 1 (BAK1) and antagonized by BCL2, apoptosis regulator (BCL2) has been shown to regulate both the cytotoxicity and immunostimulatory potential of various anticancer agents. Here, we harnessed mouse mammary carcinoma TS/A cells bearing genetic alterations that affect the molecular machinery for MOMP to demonstrate their implications in the cytotoxic effect of RT and short-term release of the cell death-related DAMPs. In our hands, RT did not induce cell death in Bax -/- Bak1 -/- TS/A cells 48 h after exposition and in contrast to wild type (WT) cells, but it completely stopped their proliferation. Moreover, (1) MOMP defects failed to alter the ability of RT to elicit the immunogenic cell death (ICD)-associated exposure of calreticulin (CALR) on the outer leaflet of the plasma membrane. Additionally, (2) MOMP-deficient cells completely reduced their ability to release ATP after RT and (3) increased the levels of the co-inhibitory ligand CD274 (best known as PD-L1) on their surface in contrast to WT cells. These results highlighted the potential involvement of MOMP in the immunogenicity of RT-driven cell death. Citation Format: Manuel Beltrán-Visiedo, Ruth Soler-Agesta, Emma Guilbaud, Ai Sato, Lorenzo Galluzzi. MOMP-dependent cytotoxicity and immunogenicity of radiation therapy in breast cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B073.