Abstract B063: The cholesterol efflux protein, ABCA1, plays a critical role in modulating anti-tumor myeloid immune cell functions

Abstract Although significant strides have been made in immune-targeting therapies such as immune checkpoint blockade (ICB), many solid tumors do not respond and acquired resistance is common, especially for metastatic disease. For example, ICB is only FDA approved for metastatic breast cancer of the triple negative subtype (TNBC) where tumors stain positive for PD-L1, but even amongst this cohort, the response rate modest. Although multifactorial, a major driver of resistance is thought to be contributed by immune suppressive myeloid immune cells, such as macrophages. Interestingly, we and others have found that regulators of cholesterol homeostasis have profound effects on myeloid cell function. Therefore, we performed in silico screens to identify potential targets that (1) are involved in cholesterol homeostasis, (2) are expressed in myeloid cells, and (3) whose expression in tumors is associated with survival. In so doing, we identified ABCA1, a protein involved in cholesterol efflux. ABCA1 was found to modulate several functions of macrophages important for tumor pathophysiology: increased ability to infiltrate tumor spheroids, decreased angiogenic potential, decreased efferocytosis, and enhanced support of CD8+ T cell expansion and their anti-cancer cytotoxic activity. Importantly, immunohistochemistry assessment of breast tumor microarrays found an inverse correlation between myeloid cell expression of ABCA1 and CD8+ cells, highlighting the clinical relevance of our results. Syngeneic mammary and melanoma tumors grew at a significantly enhanced rate in mice lacking myeloid cell ABCA1 (ABCA1+/+;LysMcre+ vs. ABCA1fl/fl;LysMcre+). Therefore, our data strongly suggest that ABCA1 is able to ‘re-educate’ myeloid immune cells towards an anti-cancer phenotype. As such, it represents a novel therapeutic target. This work was supported by the an Era of Hope Scholar Award from the Department of Defense Breast Cancer Research Program grant (BC200206) and the Cancer Center at Illinois. Citation Format: Shruti V Bendre, Natalia Krawczynska, Rajendra K C, Yu Wang, Shaunak Bhogale, Erin Weisser, Basel Hajyousif, Simon Han, Avni Singh, Claire P. Schane, Adam T. Nelczyk, Dhanya Pradeep, Anasuya Das Gupta, Lara Kockaya, Hashni Epa Vidana Gamage, Kevin Van Bortle, Emad Tajkorshid, Saurabh Sinha, Wendy A. Woodward, Wonhwa Cho, Erik R Nelson. The cholesterol efflux protein, ABCA1, plays a critical role in modulating anti-tumor myeloid immune cell functions [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 B063.