Association of clock-like mutational signature with immune checkpoint inhibitor outcome in patients with melanoma and NSCLC

Abstract

Immune checkpoint inhibitor (ICI) therapy has achieved remarkable clinical benefit in melanoma and non-small cell lung cancer (NSCLC). Tumor mutational signatures are the fingerprints of endogenous and exogenous factors that have acted throughout tumorigenesis and heterogeneity; however, their association with immune response in ICI-treated samples remains unclear. Here, we leveraged whole-exome sequencing (WES)-based mutational profiles combined with clinicopathologic characteristics from melanoma and NSCLC datasets to examine whether tumor genomic features contribute to clinical benefit of ICI treatment. Mutational data acquired from targeted next-generation sequencing (NGS) assays (MSK-IMPACT panels) were also employed for further corroboration. A mutational signature (known as age-related clock-like processing) characterized by enrichment of C>T mutations at NpCpG trinucleotides were identified to be associated with a worse prognosis and lower tumor mutation load (TML) in both WES and targeted NGS immunotherapy cohorts. We also analyzed gene transcriptomic profiles and identified immune regulation-related gene pathways that were significantly altered in samples with different clock-like signature grouping. Leucocyte subset analysis further revealed that clock-like signature was associated with the reduction of cytotoxic cell infiltration and elevation of regulatory T cells. Overall, our work re-annotated that the age-related clock-like signature was associated with worse prognosis and lower immune activity, offering opportunities to stratify patients into optimal immunotherapy plans based on genomic subtyping.

Elevated Stratifin promotes cisplatin-based chemotherapy failure and poor prognosis in non-small cell lung cancer

“… 12 , 13 , 14 Overcoming immunotherapy resistance is challenging because of the complex and dynamic interplay among malignant cells and the immune defense system. 15 , 16 , 17 , 18 …”

Mutation burden-orthogonal tumor genomic subtypes delineate responses to immune checkpoint therapy

“…On the other hand, it has been reported that high copy number, aneuploidy, and HRD-associated scores inversely correlate with tumor immune response [28][29][30] , and negative results in a recent clinical trial in ovarian cancer where half of the tumors showed HRD 31,32 suggest that HRD-related signatures are unlikely to be associated with high sensitivity to ICIs. Aging-related (clock-like) mutational signatures are reported to be associated with lower immune activity in melanoma and non-small cell lung cancer treated with ICI 9,33 . Since many age-related gene mutations also occur in non-tumor cells 34 , they may be related to immune tolerance.…”

“…Aging-related (clock-like) mutational signatures are reported to be associated with lower immune activity in melanoma and non-small cell lung cancer treated with ICI 9,32 . Since many age-related gene mutations also occur in non-tumor cells 33 , they may be related to immune tolerance.…”

Single‐cell transcriptomic analysis reveals circadian rhythm disruption associated with poor prognosis and drug‐resistance in lung adenocarcinoma

“…Recent study has shown that the clock-like mutational signature affects the outcome of ICB in patients with specific cancers. 64 This finding prompted us to extract somatic mutational profiles from TCGA datasets and annotated the clock-like signature against the Catalog of Somatic Mutations in Cancer (COSMIC) 65 (Figure S7B-D). Then, we stratified the LUAD samples into clock-like or non-clock-like subtypes in terms of mutational signature activities.…”