Progesterone receptor impairs immune respond and down-regulates sensitivity to anti-LAG3 in breast cancer

Abstract

Background

Progesterone receptor (PR) serves as a crucial prognostic and predictive marker in breast cancer. Nonetheless, the interplay between PR and the tumor immune microenvironment remains inadequately understood. This investigation employs bioinformatics analyses, mouse models, and clinical specimens to elucidate the impact of PR on immune microenvironment and identify potential targets for immunotherapy, furnishing valuable guidance for clinical practice.

Methods

Analysis of immune infiltration score by Xcell between PR-positive and PR-negative breast cancer tumors. Construction of overexpression mouse progesterone receptor (mPgr) EMT-6 cell was to explore the tumor immune microenvironment. Furthermore, anti- Lymphocyte-activation gene 3 (LAG3) therapy aimed to investigate whether PR could influence the effectiveness of immune treatments.

Results

Overexpression mPgr inhibited tumor growth in vitro, but promoted tumor growth in Balb/c mouse. Flow cytometry showed that the proportion and cytotoxicity of CD8⁺T cells in tumor of overexpressing mPgr group were significantly reduced. The significant reduction in overexpressing mPgr group was found in the proportions of LAG3⁺CD8⁺ T cells and LAG3⁺ Treg T cells. Anti-LAG3 treatment resulted in reduced tumor growth in EV group mouse rather than in overexpressing mPgr group. Patents derived tumor fragment (PDTF) also showed higher anti-tumor ability of CD3⁺T cell in patents’ tumor with PR <20% after anti-human LAG3 treatment in vitro.

Conclusions

The mPgr promotes tumor growth by downregulating the infiltration and function of cytotoxic cell. LAG3 may be a target of ER-positive breast cancer immunotherapy. The high expression of PR hinders the sensitivity to anti-LAG3 treatment.