Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification

Immunotherapy is a mainstay of non-small cell lung cancer (NSCLC) management. While tumor mutational burden (TMB) correlates with response to immunotherapy, little is known about the relationship between the baseline immune response and tumor genotype. Using single-cell RNA sequencing, we profiled 361,929 cells from 35 early-stage NSCLC lesions. We identified a cellular module consisting of PDCD1(+)CXCL13(+) activated T cells, IgG(+) plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAM(hi)). We confirmed LCAM(hi) enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAM(hi) lesions. LCAM presence was found to be independent of overall immune cell content and correlated with TMB, cancer testis antigens, and TP53 mutations. High baseline LCAM scores correlated with enhanced NSCLC response to immunotherapy even in patients with above median TMB, suggesting that immune cell composition, while correlated with TMB, may be a nonredundant biomarker of response to immunotherapy.

Automated summary

This study identified a cellular module called lung cancer activation module (LCAM(hi)) in early-stage NSCLC lesions, which consists of activated T cells, plasma cells, and macrophages, and is associated with enhanced response to immunotherapy. LCAM presence was found to be independent of overall immune cell content and correlated with TMB, cancer testis antigens, and TP53 mutations, suggesting it may serve as a nonredundant biomarker for immunotherapy response in NSCLC patients.