Abstract A048: The Loss of Cholesterol Efflux Pump ABCA1 Skews Macrophages Towards a Pro-tumor Phenotype and Facilitates Breast Cancer Progression

Abstract Breast cancer is the most common and second-leading cause of cancer-related fatalities in women in the United States. The primary cause of mortality is often the recurrence of metastatic breast cancer. While immunotherapy shows some effectiveness, it has only been approved for patients who stain positive for PD-L1. Previous research in our lab has shown that macrophage function can be regulated through disruption in cholesterol metabolism. Additionally, elevated plasma cholesterol levels have been associated with breast cancer recurrence. These findings underscore the impact of cholesterol homeostasis in tumor-associated macrophages on breast cancer progression. An in-depth computational screen helped us pinpoint ABCA1—a cholesterol efflux protein whose elevated mRNA expression linked to increased survival. In addition to efflux, ABCA1 can also translocate cholesterol from the inner leaflet of the plasma membrane to the outer layer. Highlighting the clinical importance of ABCA1 are our findings that show that increased ABCA1 levels within breast tumors correlate to an increase in cytotoxic T Cells, and T cell effector enzymes (Prf-1 and Gzmb), and improved survival rates. Importantly, our in vitro studies suggest that ABCA1 influences several functions of macrophages relevant to tumor biology. Specifically, ABCA1 shifts macrophages towards an anti-cancer phenotype by (1) increasing their ability to infiltrate tumor spheroids, (2) decreasing angiogenesis, (3) decreasing efferocytosis—an immune-suppressive phagocytic process devoid of antigen presentation, and (4) enhancing the expansion, migration, and activity of cytotoxic T cells. The culmination of these attributes were demonstrated by our observations that syngeneic grafts of E0771 mammary tumors grew at an accelerated rate in mice with a myeloid-specific knockout of ABCA1 (ABCA1fl/fl;LysMcre+) compared to control mice. ABCA1 transports cholesterol from macrophages to a lipid-poor ApoA1 protein and facilitates the formation of nascent HDL via the reverse cholesterol transport pathway. We leveraged this mechanism to therapeutically target ABCA1 using ApoA1 mimetics 5A and 4F. Our data so far indicates that ApoA1 mimetics phenocopy ABCA1 overexpression skewing macrophages towards an anti-tumor phenotype. Importantly, treatment with 5A in mice grafted with 4T1 metastatic breast cancer cell line resulted in marked reduction in tumor burden. Additionally, we observed an increased infiltration of cytotoxic T cells and a decrease in CD31 expression, suggesting reduced blood vessel formation. Collectively, our data strongly supports the role of ABCA1 in the development of breast cancer. The expected results from this research will lay the groundwork for future therapeutic strategies for the use of ABCA1 and ApoA1 mimetics in the treatment of breast cancer. Citation Format: Shruti Bendre, Natalia Krawczynska, Shaunak Bhogale, Erin Weisser, Simon Han, Basel Hajyousif, Avni Singh, Rajendra KC, Yu Wang, Claire P Schane, Adam T Nelczyk, Dhanya Pradeep, Lara Kockaya, Hashni Epa Vidana Gamage, Kevin VanBortle, Emad Tajkorshid, Saurabh Sinha, Wendy A Woodward, Wonhwa Cho, Erik R Nelson. The Loss of Cholesterol Efflux Pump ABCA1 Skews Macrophages Towards a Pro-tumor Phenotype and Facilitates Breast Cancer Progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A048.