Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Programmed death 1/programmed death ligand 1 (PD-L1) inhibitors show efficacy in PD-L1-expressing tumors.
• Clinical efficacy of PD-L1 inhibitors in EGFR-mutant cancers is unclear, while KRAS mutations suggest a positive response.

Purpose of the Study:

• To investigate PD-L1 expression and tumor-infiltrating lymphocyte (TIL) populations in non-small cell lung cancer (NSCLC) patients.
• To characterize TIL activation status in relation to EGFR and KRAS mutations in NSCLC.

Main Methods:

• Multiplexed quantitative immunofluorescence was used to analyze PD-L1 expression and TILs.
• Over 150 NSCLC patients with known mutation status were included in the study.

Main Results:

• EGFR-mutant tumors exhibited significantly lower PD-L1 expression compared to KRAS-mutant and wild-type (WT) tumors.
• KRAS-mutant tumors were more inflamed with higher CD4+, CD8+, and CD20+ TILs, which were predominantly active.
• EGFR-mutant tumors frequently displayed inactive TILs, despite lymphocyte presence, and PD-L1 expression correlated with activated EGFR signaling.

Conclusions:

• EGFR-mutant tumors possess a distinct immune microenvironment characterized by inactive TILs, potentially explaining their limited response to immunotherapy.
• PD-L1 may act as a biomarker reflecting oncogenic signaling rather than immune activation in EGFR-mutant NSCLC.
• TIL activation is associated with higher PD-L1 levels primarily in EGFR/KRAS WT tumors.