Molecular architecture of the tumor microenvironment caused by <i>BRCA1</i> and <i>BRCA2</i> somatic mutations in human lung adenocarcinoma.

Abstract

Homologous recombination repair (HRR) deficiency is associated with improved immunotherapy responses in non-small cell lung cancer (NSCLC) patients. The HRR genes <i>BRCA1</i>/<i>2</i> are key regulators of DNA repair, yet their impact on the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unclear. Using single-cell sequencing and multi-omics data, we characterized <i>BRCA1/2</i> mutation-associated transcriptional programs, immune cell composition, and functional alterations in T cells, investigating the molecular and immune architecture of BRCA-mutant LUAD patients. <i>BRCA1</i>/<i>2</i> mutations were associated with increased genomic instability and poor prognosis in LUAD patients, but predicted better clinical outcomes following immune checkpoint blockade (ICB) treatment. <i>BRCA1</i> mutations correlated with an upregulated type I IFN/IFN-γ signature and CD8⁺ T cell activation. <i>BRCA2</i> mutations were associated with alveolar/stress/inflammatory responses and enhanced MHC-II antigen presentation, linked to CD4⁺ T cell differentiation. Both alterations coincided with reduced CD28 co-stimulation and CTL activity, hinting at immune evasion. We identified two tissue-resident memory T cell (Trm) subsets as predictors of clinical outcomes and ICB response. <i>BRCA1</i> mutations were associated with CD8⁺ Trm expansion, whereas <i>BRCA2</i> mutations were linked to tumor CD4⁺ Trm expansion and peripheral T/NK cell cytotoxicity. Furthermore, a cancer-promoting program activated by <i>BRCA1</i> mutation was vulnerable to histone deacetylase inhibitors, which inhibited LUAD tumor growth. This study provides a preliminary characterization of the BRCA-mutant TME in LUAD patients, revealing distinct transcriptional and immune patterns that highlight differences in <i>BRCA1/2</i>-associated molecular architecture and offer a framework for improving therapy efficacy in LUAD.