HLA-I Evolutionary Divergence Confers Response to PD-1 Blockade plus Chemotherapy in Untreated Advanced Non-Small...

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• PD-1 blockade plus chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC).
• Predictive biomarkers for this treatment combination are still needed.

Purpose of the Study:

• To investigate the predictive and prognostic value of HLA class I evolutionary divergence (HED) in NSCLC patients treated with first-line PD-1 blockade plus chemotherapy.
• To explore the association between HED and tumor microenvironment characteristics.

Main Methods:

• Integrated clinical, genomic, and survival data from 427 NSCLC patients in two phase III trials (CameL and CameL-sq).
• Analyzed HLA class I evolutionary divergence (HED) as a predictive biomarker.
• Utilized multivariate analysis, adjusting for PD-L1 expression and tumor mutation burden.
• Performed single-cell RNA sequencing on samples from 11 patients.

Main Results:

• High HED significantly predicted improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients receiving PD-1 blockade plus chemotherapy, but not chemotherapy alone.
• High HED was independently associated with better ORR, PFS, and OS, even after adjusting for PD-L1 and tumor mutation burden.
• Combined HED and PD-L1 expression demonstrated superior predictive performance compared to either biomarker alone.
• Tumors with high HED exhibited enhanced antigen presentation and T cell-mediated immunity, suggesting an inflamed tumor microenvironment.

Conclusions:

• High HED is a promising biomarker for predicting survival benefits in advanced NSCLC patients treated with first-line PD-1 blockade plus chemotherapy.
• HED may indicate an inflamed tumor microenvironment conducive to immunotherapy response.