THU490 Role Of Cholesterol Efflux Pump ABCA1 In Macrophages And Subsequent Modulation Of The Tumor Microenvironment
Authors: Bendre Shruti V , Krawczynska Natalia , Bhogale Shounak , Gupta Anasuya Das , Nelczyk Adam , Vidana Gamage Hashni Epa , Han Simon , Tajkhorshid Emad , Sinha Saurabh , Cho Wonhwa , Nelson Erik Russell 
Published: October 2023

Disclosure: S.V. Bendre: None. N. Krawczynska: None. S. Bhogale: None. A. Das Gupta: None. A. Nelczyk: None. H. Vidana Gamage: None. S. Han: None. E. Tajkhorshid: None. S. Sinha: None. W. Cho: None. E.R. Nelson: None.

Breast cancer constitutes about 30% of all new female cancers each year. Although there has been an overall decrease in death rates, mortalities associated with recurrent metastatic cancer remain high. Hence, development of targeted therapeutics against metastatic breast cancer is of utmost importance. Although breast cancer is generally considered immunologically “cold”, clinical studies have shown that immunotherapy has potential to improve patient outcomes. One of the challenges of immunotherapy is overcoming the highly immune suppressive tumor microenvironment. Myeloid cells, such as macrophages, which are abundant within the tumor micro-environment, play a key role in cancer cell survival, progression, and metastasis. Several aspects of cholesterol metabolism and regulation have been implicated in breast cancer progression. ABCA1 (ATP Binding Cassette subfamily A member 1) is a membrane bound cholesterol efflux protein, which facilitates cholesterol transport across, as well as between, membrane leaflets. Although implicated in macrophage biology, little is known about how ABCA1 impacts macrophage function in terms of tumor biology. Therefore, the goal of the current work is to determine the effect of altering ABCA1 within macrophages and its subsequent effect on the tumor microenvironment. Intriguingly, our analysis of publicly available transcriptomes indicates that ABCA1 expression within breast tumors is associated with good prognosis, supporting a role for ABCA1 in tumor progression. Important aspects of macrophage function are efferocytosis, antigen presentation, interaction with and activation of T cells, and promotion of angiogenesis. Therefore, we investigated each of these aspects under conditions where ABCA1 expression was manipulated. Our results indicate that knocking down ABCA1 in macrophages decreased the activation and expansion of T cells. Those T cells that were activated, had a decreased anti-cancer cytotoxic response. Over expression of ABCA1 had the opposite effects, supporting our conclusion that ABCA1 in macrophages is critical for normal T cell activation and function. Furthermore, we are finding that ABCA1 is involved in several other aspects of macrophage biology with relevance to tumor progression. Specifically, knockdown of ABCA1 increased the efficiency of efferocytosis, increased angiogenesis, and decreased macrophage infiltration into breast cancer organoids. All these activities suggest that the loss of ABCA1 shifts macrophages into a functional state that is immune-suppressive and pro-tumorigenic. In summary, our results to date indicate that ABCA1 expression within macrophages reduces their pro-tumor functions. Therefore, it will be important to explore this biology in the hopes of developing ABCA1 as a therapeutic target to shape the tumor microenvironment into being less permissive to tumor growth.

Presentation: Thursday, June 15, 2023