Activating mutations in ESR1 contribute to an immunosuppressive breast tumor microenvironment.

Estrogen receptor (ER, ESR1)-positive breast cancer patients are most at risk of long-term relapse, where activating somatic mutations in ESR1 promote metastasis and therapeutic resistance. ER+ patients are also disadvantaged in receiving and responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a novel transgenic mouse model carrying either Y541S or D542G point mutation in ESR1, mirroring the two most common mutations in ER+ metastatic breast cancer patients. End-stage ESR1mut tumors do not differ in the total number of immune cells yet display downregulation in immune-mediated pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1b. Furthermore, T cells and macrophages have lower IFNγ activity and antigen presentation, respectively. Mechanistically, ESR1mut negatively regulates immune modulator expression compared to wild-type ESR1 and upregulates Stat5 to further dampen cytokine expression. In concordance, clinical validation on ESR1mut patient tumors shows decreased IL-17a and IL-1b. Collectively, our findings reveal that activating mutations in ER contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity, supporting clinical observations where hormone receptor patients, especially ER mutant patients, respond poorly to immunotherapies.