DNA methyltransferase 3A (DNMT3A) mutations and PD-(L)1 blockade efficacy in non-small-cell lung cancer

Abstract

Background: Despite significant improvements in overall survival with programmed cell death protein (ligand) 1 [PD-(L)1] inhibition, most patients with metastatic non-small-cell lung cancer (NSCLC) do not respond to immune checkpoint inhibition (ICI). Growing evidence suggests the importance of genomic alterations in modulating anticancer immune response and predicting ICI efficacy. However, the genomic correlates of response to ICI in NSCLC are largely unknown.

Design: Patients with advanced NSCLC treated with ICI and comprehensive genomic profiling from multiple independent cohorts were included. Beta-binomial modelling of sequencing read counts was used to infer mutation clonality. NSCLC samples from Cancer Genome Atlas Program (TCGA) and NSCLC cell lines from Cancer Cell Lines Encyclopedia (CCLE) were used for transcriptomic analyses.

Results: Among 1539 NSCLCs, we identified deleterious DNA methyltransferase 3A (DNMT3A) mutations in 4.7% of cases. Patients with DNMT3A-mutant NSCLC had improved response rate (41.7% versus 21.5%, P < 0.001), progression-free survival [hazard ratio (HR) 0.61, P < 0.001], and overall survival (HR 0.66, P < 0.01) with PD-(L)1 blockade, compared with DNMT3A wild-type cases. DNMT3A mutations had no impact on OS among patients with advanced NSCLC who did not receive ICI (HR 0.88, P = 0.41). In examining the impact of DNMT3A clonality on immunotherapy outcomes to account for potential clonal hematopoiesis of indeterminate potential contamination, we confirmed that clonal DNMT3A mutations were associated with improved outcomes compared with DNMT3A wild-type cases. In NSCLC cell lines with pathogenic DNMT3A mutations, DNMT3A RNA and protein expression were decreased. In the TCGA, NSCLCs with high versus low DNMT3A expression exhibited lowered expression of pathways involved in innate and adaptive immune response, including interferon-γ (INFγ), major histocompatibility complex (MHC)-II antigen presentation, tumor necrosis factor-α (TNF-α), and PD-1 signaling.

Conclusion: Somatic DNMT3A mutations can be detected in a fraction of NSCLCs and are associated with a decreased DNMT3A expression and a favorable immunophenotype, and predict improved ICI efficacy.

Keywords: DNMT3A mutations; PD-(L)1 inhibition; comprehensive tumor genomic profiling; non-small-cell lung cancer (NSCLC); predictive biomarkers in immunotherapy response.