Deciphering Microenvironment of NSCLC based on CD8+ TIL Density and PD-1/PD-L1 Expression

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• The tumor immune microenvironment (TIM) significantly influences non-small cell lung cancer (NSCLC) progression and treatment response.
• Understanding the interplay between immune cells (TILs) and immune checkpoint molecules (PD-1/PD-L1) is crucial for effective cancer immunotherapy.

Purpose of the Study:

• To investigate if distinct tissue immune microenvironments differentially impact clinical outcomes in NSCLC.
• To analyze the prognostic value of PD-1/PD-L1 expression and CD8+ Tumor Infiltrating Lymphocytes (TILs) in NSCLC patients.

Main Methods:

• Utilized mRNA-sequence data from 1016 NSCLC samples (TCGA) and mRNA-microarray data from 275 NSCLC samples (GEO).
• Quantified CD8+ T cell infiltration using enrichment scores and classified patients into four Tumor Immune Microenvironment types (TIMTs) based on CD8+ TIL density and PD-1/PD-L1 expression.
• Compared overall survival, clinicopathological features, and mutational profiles across the four TIMTs.

Main Results:

• PD-1 or PD-L1 expression alone did not correlate with NSCLC patient outcomes.
• TIMT classification effectively stratified survival in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). TIMT3 (high CD8+ TIL, low PD-1/PD-L1) showed the best survival, while TIMT2 (low CD8+ TIL, high PD-1/PD-L1) had the worst.
• PD-1/CD8+ TIL classification was a better prognostic indicator than PD-L1/CD8+ TIL. TIMT4 (high PD-1/PD-L1, high CD8+ TIL) was associated with EGFR wild type and IFNγ overexpression.

Conclusions:

• Classifying NSCLC into four TIMT subtypes based on PD-1/PD-L1 status and CD8+ TIL density is a valid approach for patient stratification.
• This classification system can help guide the clinical application of immunotherapy in NSCLC.
• The immune microenvironment's composition is a critical determinant of clinical outcome in NSCLC, particularly in adenocarcinoma subtypes.