Targeting IL27RA Enhances Immunotherapy in Triple-Negative Breast Cancer by Modulating Tumor Cells and the Tumor...

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Immune checkpoint blockade (ICB) shows promise for triple-negative breast cancer (TNBC), but resistance is a significant challenge.
• The molecular mechanisms underlying ICB resistance in TNBC require further elucidation.

Purpose of the Study:

• To investigate the molecular drivers of ICB resistance in TNBC.
• To identify novel therapeutic targets for overcoming immunotherapy resistance in TNBC.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of paired pre- and post-neoadjuvant PD-1 therapy tumor samples from TNBC patients (non-pCR and pCR cohorts).
• Analysis of IL27RA expression in relation to treatment response and patient survival.
• Mechanistic studies involving the PI3K/AKT pathway and MHC-I expression.
• Inhibition of AKT in preclinical tumor models.
• Orthotopic tumor models in immunocompetent mice.

Main Results:

• Upregulation of interleukin-27 receptor subunit alpha (IL27RA) in malignant epithelial cells of residual TNBC tumors after PD-1 therapy (non-pCR).
• IL27RA upregulation is largely restricted to non-pCR residual tumors and correlates with poor survival.
• IL27RA suppresses MHC-I expression via the PI3K/AKT pathway, impairing CD8+ T-cell function.
• AKT inhibition restored T-cell killing; Il27ra deficiency in models reduced tumor growth and enhanced anti-tumor immunity.

Conclusions:

• An epithelial-intrinsic IL27RA-PI3K/AKT-MHC-I axis drives immune evasion and ICB resistance in TNBC.
• IL27RA represents a promising therapeutic target to enhance immunotherapy efficacy in TNBC.