Neoantigen-directed immune escape in lung cancer evolution

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• The dynamic interplay between evolving cancers and the immune microenvironment is not fully understood.
• Early-stage, untreated non-small-cell lung cancer (NSCLC) presents a critical window to study these interactions.
• Tumor-infiltrating lymphocytes (TILs) are key components of the immune microenvironment influencing cancer progression.

Purpose of the Study:

• To investigate the relationship between immune infiltration and tumor evolution in early-stage NSCLC.
• To identify mechanisms of immune evasion driven by the tumor microenvironment.
• To determine the clinical relevance of these immune evasion strategies.

Main Methods:

• Analysis of 258 tumor regions from 88 early-stage NSCLC patients.
• Utilized RNA sequencing and histopathology for TIL estimation.
• Examined neoantigen presentation, human leukocyte antigen (HLA) status, and gene promoter methylation.

Main Results:

• Immune infiltration varied significantly within and between tumors.
• Distinct immune microenvironments were associated with different neoantigen presentation defects.
• Mechanisms of immune evasion included historical immune editing, copy-number loss, HLA loss of heterozygosity, neoantigen depletion, and epigenetic silencing via promoter hypermethylation.
• Promoter hypermethylation of neoantigenic genes was identified as an epigenetic immunoediting mechanism.

Conclusions:

• The immune microenvironment exerts strong selection pressure on early-stage NSCLC.
• Multiple pathways to immune evasion are established through tumor evolution.
• These immune evasion mechanisms are clinically relevant and associated with poor disease-free survival.