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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Progesterone receptor (PR) is a key marker in breast cancer prognosis and prediction.
• The relationship between PR and the tumor immune microenvironment is not fully understood.
• This study aims to clarify PR's impact on the immune microenvironment and identify immunotherapy targets.

Purpose of the Study:

• To investigate the effect of progesterone receptor (PR) on the tumor immune microenvironment in breast cancer.
• To explore PR's influence on the efficacy of immune checkpoint inhibitor therapy.
• To identify potential therapeutic targets for breast cancer immunotherapy.

Main Methods:

• Bioinformatic analysis of immune infiltration scores (Xcell) in PR-positive versus PR-negative tumors.
• Development of a mouse model with overexpressed mouse progesterone receptor (mPgr) in EMT-6 cells.
• Assessment of anti-Lymphocyte-activation gene 3 (LAG3) therapy efficacy in mouse models and patient-derived tumor fragments.

Main Results:

• Overexpression of mPgr inhibited in vitro tumor growth but promoted it in vivo in mice.
• mPgr overexpression led to reduced proportions and cytotoxicity of CD8+ T cells.
• Significant reductions in LAG3+ CD8+ T cells and LAG3+ Treg T cells were observed with mPgr overexpression.
• Anti-LAG3 therapy was less effective in mPgr-overexpressing tumors compared to controls.
• Tumor fragments with low PR (<20%) showed enhanced anti-tumor CD3+ T cell activity after anti-human LAG3 treatment.

Conclusions:

• Overexpressed PR promotes tumor growth by suppressing cytotoxic T cell infiltration and function.
• Lymphocyte-activation gene 3 (LAG3) presents a potential therapeutic target for ER-positive breast cancer immunotherapy.
• High progesterone receptor (PR) expression diminishes sensitivity to anti-LAG3 immunotherapy.