Abstract A43: Exploiting off-target effects of estrogen receptor-targeting drugs to sensitize breast cancer to immune killing

Abstract

Abstract 1 in 8 women will be diagnosed with breast cancer within their lifetime. The majority of women are diagnosed with estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or HER2+ breast cancers. The standard of care for ER+ breast cancer is treatment with selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) drugs. While these are highly effective for ER+ breast cancers and additional targeted drugs exist for PR+ and HER2+ cancers, there are currently no targeted therapeutic strategies for the 10-15% of women who are diagnosed with triple-negative breast cancer (TNBC). We hypothesize that estrogen receptor-targeting drugs are capable of inducing phenotypic changes to sensitize breast tumor cells to immune-mediated killing regardless of their ER status. In this study, we used in vitro killing assays and molecular characterization of ER+ and ER- cell lines to identify that SERM and SERD drugs sensitize breast cancer to killing by healthy-donor natural killer (NK) cells regardless of their ER status. While tamoxifen (SERM) and fulvestrant (SERD) had no cytotoxic or antiproliferative effect on ER- cells, pretreatment with either resulted in increased NK-mediated cell lysis. Through RNAseq analysis of tamoxifen-treated ER+ and ER- cells, we identified increased activation of both apoptotic and death receptor signaling pathways. These pathways play a key role in immunogenic modulation, indicating a potential mechanism for tamoxifen-induced tumor sensitization to immune cell lysis. It has previously been reported that in addition to binding to ER, both tamoxifen and fulvestrant bind to G protein-coupled estrogen receptor 1 (GPR30). We found that GPR30 is expressed in both ER+ and ER- breast cancer cells. Using the specific GPR30 agonist G-1, we demonstrated that targeted activation of GPR30 signaling resulted in increased NK cell killing. These data indicate that the observed ER-independent immunogenic modulation of breast cancer cells may be occurring through GPR30. Together, these findings demonstrate a novel effect of SERM and SERD drugs on the interaction between both ER+ and ER- tumor cells with the immune system. This study is the first to demonstrate the potential use of ER-targeting drugs in immunotherapy combinations in an ER-agnostic manner and may inform novel immunotherapy strategies in breast cancer. Citation Format: Benjamin Wolfson, Jeffrey Schlom, James Hodge. Exploiting off-target effects of estrogen receptor-targeting drugs to sensitize breast cancer to immune killing [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A43.