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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.

SUBMITTER: Chong W

PROVIDER: S-EPMC7723771 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Chong Wei W Wang Zhe Z Shang Liang L Jia Shengtao S Liu Jin J Fang Zhen Z Du Fengying F Wu Hao H Liu Yang Y Chen Yang Y Chen Hao H

Molecular therapy. Nucleic acids 20201027

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 melan ...[more]

PMID: 33335795

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Project description:ImportanceImmune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment and are now standard of care. Although sex is associated with immune function and immune-related diseases, the interaction between sex and ICIs is understudied.ObjectiveTo examine whether cancer immunotherapy effectiveness varies between female and male patients with advanced melanoma treated with either nivolumab plus ipilimumab combination therapy or anti-programmed cell death protein 1 (PD-1) therapy (namely, pembrolizumab or nivolumab).Design, setting, and participantsThe study population consisted of 1369 older adults (aged ≥65 years) with a record of melanoma diagnosis from January 1, 1991, to December 31, 2015, in the Surveillance, Epidemiology, and End Results-Medicare linked database. Patients with a diagnosis of stage III or stage IV melanoma and a claims record showing nivolumab plus ipilimumab combination therapy or anti-PD-1 therapy (ie, pembrolizumab or nivolumab) as their last type of ICI prescribed were included in the analyses. Patients were followed up through December 31, 2017, for the overall survival analysis. Statistical analysis was performed from September 19, 2019, to February 20, 2021.ExposuresSex, last prescribed ICI, and prior use of ipilimumab.Main outcomes and measuresThe primary outcome was overall survival, defined as time from the index date until death from any cause, with patients censored at the end of the study (December 31, 2017). Cox proportional hazards regression modeling was used to examine the association of sex with ICI outcomes while adjusting for prior use of ipilimumab, age at ICI initiation, Charlson Comorbidity Index, cancer stage at the time of diagnosis, and autoimmune disease diagnosis.ResultsAmong the 1369 patients in the study (982 men [71.7%]; median age, 75 years [IQR, 69-82 years]), the outcome of nivolumab plus ipilimumab combination therapy depended on sex (Wald χ2 = 9.48; P = .009 for interaction). The mortality hazard ratio (HR) for women with prior ipilimumab use receiving combination therapy was 2.06 times (95% CI, 1.28-3.32; P = .003) higher than their male counterparts. No significant difference was observed between women and men receiving anti-PD-1 therapy with (HR, 0.97 [95% CI, 0.68-1.38]; P = .85) or without prior ipilimumab use (HR, 0.85 [95% CI, 0.67-1.07]; P = .16). For women with prior ipilimumab use, combination therapy was associated with 2.82 times higher mortality hazards than anti-PD-1 therapy (95% CI, 1.73-4.60). No statistically significant difference was seen in mortality risk between anti-PD-1 therapy and combination therapy for men.Conclusions and relevanceThis cohort study suggests that female patients with advanced melanoma may not benefit as much from combination ICIs as male patients would. Tumor mutation burden or estrogen level may serve as an important biomarker associated with ICI response in metastatic melanoma.

Dataset Information

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

Publications

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

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