# Activating mutations in ESR1 contribute to an immunosuppressive breast tumor microenvironment by dampening cytokine secretion

## TL;DR

Breast tumors with ESR1 mutations reduce immune-boosting cytokines, leading to a less active immune response and a more immunosuppressive tumor environment.

## Contribution

A new mouse model reveals how ESR1 mutations in breast cancer dampen immune responses by reducing cytokine secretion and immune cell activity.

## Key findings

- ESR1 mutations decrease immune-modulatory cytokines like IL-17a and IL-1β.
- T cells and macrophages show reduced IFN-γ and antigen presentation in ESR1-mutated tumors.
- ESR1 mutations upregulate Stat5 to suppress cytokine expression and immune pathways.

## Abstract

Patients with estrogen receptor+ (ER+, ESR1+) breast cancer are most at risk of relapse, where activating mutations in ESR1 promote metastasis and therapeutic resistance. These patients are also disadvantaged in responding to immunotherapies, the mechanisms of which remain to be elucidated. Here, we engineered a transgenic mouse model carrying either Y541S or D542G mutation in ESR1, mirroring the 2 most common mutations seen in patients. ESR1mut tumors do not differ in the total number of immune cells yet display downregulation in immune pathways and decreased immune-modulatory cytokines, including IL-17a and IL-1β. T cells and macrophages have lower IFN-γ and antigen presentation, respectively. Mechanistically, ESR1mut negatively regulates immune modulator expression and upregulates Stat5 to dampen cytokine expression. In concordance, validation on ESR1mut patient tumors shows decreased IL-17a and IL-1β. Collectively, our findings reveal that ESR1 mutations contribute to an immunosuppressive tumor microenvironment by dampening cytokine secretion and immune cell activity.

Breast tumors with ESR1 mutations release fewer immune‑boosting cytokines, creating a tumor microenvironment where immune cells have limited ability to eliminate cancer cells.