Mutation-Driven Immune Microenvironments in Non-Small Cell Lung Cancer: Unrevealing Patterns through Cluster Analysis

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Non-small cell lung cancer (NSCLC) is a leading cause of cancer death.
• Tumor heterogeneity significantly impacts treatment response.
• Single-cell RNA sequencing (scRNA-seq) offers high-resolution insights into complex biological systems.

Purpose of the Study:

• To comprehensively analyze the tumor microenvironment (TME) at the single-cell level.
• To identify tumor heterogeneity driven by major oncogene mutations in NSCLC.
• To correlate specific mutations with immune cell and stromal components.

Main Methods:

• Utilized scRNA-seq data from 64,369 primary tumor cells across 21 NSCLC patients.
• Focused on mutations in EGFR, ALK, BRAF, KRAS, TP53, and wild-type.
• Performed detailed analysis of immune cell and stromal components within the TME.

Main Results:

• Identified two distinct mutation clusters (MC1: KRAS, TP53, EGFR+TP53; MC2: EGFR, BRAF, ALK) with differential immune responses.
• MC1 exhibited higher tertiary lymphoid structures and specific immune cell populations (T/NK, B cells).
• MC2 showed enrichment of inflammatory cytokines (TNF, IL1B) and alternative immune pathways. EGFR+TP53 mutations displayed distinct cellular activity and differentiation profiles compared to EGFR mutations.

Conclusions:

• Mutation type is closely associated with the tumor microenvironment in NSCLC.
• These findings provide a basis for developing personalized diagnostic and therapeutic strategies.
• Single-cell analysis reveals critical TME differences linked to specific oncogenic drivers.