Abstract 2515: Estrogen regulates the immune microenvironment of colorectal cancer liver metastases

Liver metastases (LM) remain a major cause of cancer-related death and many cancers preferably metastasize to the liver due to its unique anatomical location, rich blood supply and immune-tolerant microenvironment. Up to 50% of colorectal carcinoma patients develop LM during their disease and this is associated with a poor prognosis. Our laboratory previously identified a sexual dimorphism in the regulation of the immune microenvironment (IME) of LM and showed that estrogen could promote the accumulation of myeloid-derived suppressor cells (MDSCs) and Tregs in the liver in response to invading cancer cells. The objective of this study was to elucidate the role of estrogen in the recruitment and polarization of monocytes/macrophages and in the accumulation and phenotype of natural killer (NK) cells in the IME of colorectal carcinoma LM (CRCLM). Moreover, we sought to determine the therapeutic potential of Selective Estrogen Receptor Degrader (SERD) therapy in tumor bearing female mice. In estrogen-competent female mice bearing CRCLM, we found increased gene and protein expression of the immunosuppressive cytokine TGF-β, and inversely a decrease in the pro-inflammatory cytokine TNF-alpha. Furthermore, we identified a significant increase of newly recruited, immunosuppressive CD68+F4/80+CD163+ M2 macrophages, as compared to estrogen-depleted (ovariectomized) mice. The recruitment of pro-inflammatory CD68+F4/80+TNF-alpha+ M1 macrophages, and the accumulation of the highly cytotoxic NK1.1+ CD49a+ liver NK cells were increased in estrogen-depleted female mice and could be restored upon estrogen supplementation. Moreover, treatment of female mice with the SERD Fulvestrant, markedly reduced the number of CRCLM compared to vehicle-treated mice, and significantly reduced the cell frequencies and counts of recruited myeloid cells and M2 macrophages in the liver. Taken together, our results identify estrogen as a critical regulator of an immunosuppressive tumor ME in the liver and a potential therapeutic target. Funding by the Canadian Institute of Health Research is gratefully acknowledged. Citation Format: Yasmine Benslimane, Sarah Lapin, Julien Chambon, Matthew Leibovitch, Stéphanie Perrino, Pnina Brodt. Estrogen regulates the immune microenvironment of colorectal cancer liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 25