Autocrine 17-β-Estradiol/Estrogen Receptor-α Loop Determines the Response to Immune Checkpoint Inhibitors in...

Area of Science:

• Oncology
• Immunology
• Endocrinology

Background:

• Immune checkpoint inhibitors (ICI) show variable efficacy in non-small cell lung cancer (NSCLC) between genders, with controversial meta-analyses and undefined mechanisms.
• Understanding gender-specific responses to anti-PD-1/anti-PD-L1 therapy is crucial for optimizing NSCLC treatment.

Purpose of the Study:

• To elucidate the molecular mechanisms behind differential gender-related responses to anti-PD-1/anti-PD-L1 agents in NSCLC.
• To identify predictive biomarkers for ICI efficacy in NSCLC patients.

Main Methods:

• Prospective analysis of NSCLC patients treated with first-line ICI.
• In vitro molecular mechanism identification in NSCLC cell lines.
• In vivo validation using patient-derived xenografts with human reconstituted immune systems (immune-PDXs).

Main Results:

• Estrogen receptor alpha (ERα) emerged as a stronger predictor of pembrolizumab response than gender or PD-L1 levels.
• ERα upregulates CD274/PD-L1 gene expression, particularly in female patients, via 17-β-estradiol and EGFR-downstream pathways (Akt, ERK1/2).
• Aromatase inhibitor letrozole significantly enhanced pembrolizumab efficacy in immune-PDXs by reducing PD-L1 and increasing anti-tumor T and NK cells, with maximal benefit in ERα-high female models.

Conclusions:

• 17-β-estradiol/ERα status is a predictive biomarker for pembrolizumab response in NSCLC.
• Aromatase inhibitors represent a novel strategy for gender-tailored immunotherapy in NSCLC.