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

Wei Chong; Zhe Wang; Liang Shang; Shengtao Jia; Jin Liu; Zhen Fang; Fengying Du; Hao Wu; Yang Liu; Yang Chen; Hao Chen

doi:10.1016/j.omtn.2020.10.033

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

Mol Ther Nucleic Acids. 2020 Oct 27:23:89-100. doi: 10.1016/j.omtn.2020.10.033. eCollection 2021 Mar 5.

Authors

Wei Chong^{1

2

3}, Zhe Wang⁴, Liang Shang^{1

2

3}, Shengtao Jia⁵, Jin Liu⁶, Zhen Fang^{2

3}, Fengying Du^{2

3}, Hao Wu^{2

3}, Yang Liu^{2

3}, Yang Chen⁷, Hao Chen⁸

Affiliations

¹ Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
² Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.
³ Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong 250021, China.
⁴ Tianjin Sino-US Diagnostics Co., Ltd, Tianjin 300060, China.
⁵ Department of Tumor Cell Biology, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
⁶ Department of Gastroenterology, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong 250021, China.
⁷ Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
⁸ Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong 250021, China.

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.

Keywords: NSCLC; clock-like signature; immune infiltration; melanoma; prognosis; tumor mutation load.