Cholesterol efflux protein, ABCA1, supports anti-cancer functions of myeloid immune cells

• DOI: 10.1101/2025.02.19.638515
• Publication Date: 2025-02-20T02:00:14Z
• Authors: Shruti V. Bendre; Yu Wang; Basel Hajyousif; K C Rajendra; Shounak G. Bhogale; Dhanya Pradeep; Natalia Krawczynska; Claire P. Schane; Erin Weisser; Avni Singh; Simon Han; Hannah Kim; Lara Kockaya; Anasuya Das Gupta; Adam T. Nelczyk; Hashni Epa Vidana...; Yifan Fei; Xingyu Guo; Ryan J. Deaton; Maria Sverdlov; Peter H. Gann; Saurabh Sinha; Kun Wang; Kevin Van Bortle; Emad Tajkorshid; Wendy A. Woodward; Wonhwa Cho; Erik R. Nelson
• Keywords: Efflux

ABSTRACT Although immune therapy has seen significant advances, the majority of breast and other solid tumors do not respond or quickly develop de novo resistance. One factor driving resistance is highly suppressive myeloid cells (MCs) such as macrophages. Previous work established clinical links between cholesterol cancer outcome, that MC function can be regulated through disruption in metabolism. Thus, we screened for proteins were expressed MCs, involved homeostasis whose expression was associated with survival; identify efflux protein ABCA1. Preclinical studies revealed ABCA1 activity resulted increased anti-cancer functions macrophages: enhanced tumor infiltration, decreased angiogenic potential, reduced efferocytosis, improved support CD8+ T cell activity. Mechanistically, different AKT isoforms are involved, both PI3K dependent independent mechanisms. Assessment human blood correlations macrophages VEGFA , CD8 abundance activity, highlighting relevance our findings. The culmination effects on demonstrated growth metastasis mice specific knockout Therefore, modulating within MCs may represent a novel approach to therapy.