A Dysfunctional T-cell Gene Signature for Predicting Nonresponse to PD-1 Blockade in Non-small Cell Lung Cancer That...

Area of Science:

• Oncology
• Immunotherapy
• Biomarker Development

Background:

• PD-1 blockade efficacy is limited in advanced non-small cell lung cancer (NSCLC).
• Predictive biomarkers are crucial for guiding immunotherapy decisions.
• Tumor-infiltrating lymphocytes (TILs) expressing PD-1 (PD-1T TILs) are a validated biomarker detected by IHC.

Purpose of the Study:

• To develop a robust RNA signature that reflects PD-1T TIL status in NSCLC tumors.
• To create a gene expression assay for predicting response to PD-1 blockade therapy.
• To facilitate the clinical translation of PD-1T TILs as a predictive biomarker.

Main Methods:

• mRNA expression analysis using NanoString nCounter platform on NSCLC tumor samples.
• Development of a predictive gene signature using a training cohort (n=41) and validation in a separate cohort (n=42).
• Analysis correlated gene signature with disease control at 12 months (DC 12 m), progression-free survival, and overall survival.

Main Results:

• A 12-gene RNA signature was identified, differentiating between PD-1T IHC-high and PD-1T IHC-low tumors.
• In the validation cohort, the signature achieved 100% sensitivity and 100% negative predictive value for DC 12 m.
• The signature correctly classified 64% of progressive disease cases, demonstrating high accuracy.

Conclusions:

• The PD-1T mRNA signature demonstrates high sensitivity and negative predictive value, comparable to IHC detection of PD-1T TILs.
• This RNA signature offers a straightforward and easily implementable approach for routine clinical diagnostics.
• The findings support the use of an RNA-based assay for predicting PD-1 blockade response in NSCLC.