Immunosuppressive Tumor Microenvironment Signatures Predict Early Progression in NSCLC Patients Receiving Immune...

Area of Science:

• Oncology
• Immunology
• Transcriptomics

Background:

• Early progression (PFS < 90 days) in non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) is a significant clinical challenge.
• Predictive biomarkers for ICI response are sought, but transcriptomic and immune microenvironment features driving early progression are not well understood.

Purpose of the Study:

• To characterize transcriptomic and immune microenvironment signatures associated with early progression in NSCLC patients treated with anti-PD-1/PD-L1 therapy.
• To develop and evaluate an immunosuppressive risk score for predicting progression-free survival (PFS).

Main Methods:

• RNA-sequencing data from 27 NSCLC patients (17 early progression, 10 clinical benefit) treated with anti-PD-1/PD-L1 therapy were analyzed.
• Gene Set Enrichment Analysis (GSEA) was performed using Hallmark and C7 ImmuneSigDB gene sets.
• An 87-gene immunosuppressive risk score was derived from TGF-β, WNT/β-catenin, and EMT pathway genes.

Main Results:

• GSEA identified enriched immunosuppressive (TGF-β, WNT/β-catenin) and oncogenic (MYC, E2F, G2M) pathways in early progressors.
• Immune signatures associated with CD8 T cell dysfunction, Treg activation, and M2 macrophage polarization were enriched.
• The 87-gene immunosuppressive risk score significantly correlated negatively with PFS (Spearman ρ = -0.516, p = 0.006).

Conclusions:

• Early progression in NSCLC patients on ICI therapy is associated with co-activation of immunosuppressive, oncogenic, and T cell dysfunction pathways.
• The 87-gene immunosuppressive risk score is a promising exploratory biomarker for predicting PFS in this patient population.
• Prospective validation in independent cohorts is warranted due to the small sample size and exploratory nature of the findings.