Abstract 4919: Estrogen regulates the immune microenvironment and immunotherapy response of colorectal liver metastases

Abstract 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 other immune cells and to determine the therapeutic potential of Selective Estrogen Receptor Degrader (SERD) therapy in CRCLM bearing female mice, and evaluate if SERD would improve anti PD-1 immunotherapy efficacy. 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 decrease of immunosuppressive CD68+CD163+ M2 macrophages, and an increase of the pro-inflammatory CD68+TNF-alpha+ M1 macrophages in estrogen-depleted (ovariectomized) mice as compared to estrogen-competent mice. This observation was reversed upon estradiol supplementation. Moreover, treatment of female mice with the SERD Fulvestrant, markedly reduced the number of CRCLM compared to vehicle-treated mice, reduced the cell frequencies and counts of M2 macrophages, significantly increased NK cells recruitment in the liver. The addition of SERD to immunotherapy has a better therapeutic effect than both therapies alone, and increased CD8+ T-cells, NK cells, and M1/M2 macrophages ratio. Taken together, our results identify estrogen as a critical regulator of an immunosuppressive TME in the liver and a potential therapeutic target to enhance immunotherapy efficacy. Citation Format: Yasmine Benslimane, Sarah Lapin, Julien Chambon, Stephanie Perrino, Pnina Brodt. Estrogen regulates the immune microenvironment and immunotherapy response of colorectal liver metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4919.