Genomic and transcriptomic analyses of melanoma in Japanese patients reveal candidate biomarkers for immune checkpoint inhibitor responders

Immune checkpoint inhibitors (ICIs) have greatly improved advanced melanoma prognosis. However, the efficacy of ICIs in Japanese patients has been found to be lower than that in their white counterparts. We aimed to elucidate the genomic and transcriptomic features associated with response to ICIs in Japanese patients with melanoma. A total of 129 tumor samples were collected from 78 patients with melanoma who received therapeutic regimens with or without ICI treatment. We performed exome and RNA sequencing and investigated the association between genomic and transcriptomic factors and the clinical efficacy of ICI. The number of somatic SNVs in Japanese patients with melanoma is lower than that in the TCGA white data owing to the biased distribution of WHO subtypes. The driver subtypes BRAF, NRAS, and NF1 are less prevalent, but the triple wildtype predominantly exists in this cohort. An exome-wide survey reveals no significant association of mutated genes with ICI response; however, transcriptomic analysis reveals inflammation-associated genes, including several chemokines and cytokines, that are highly expressed in clinically benefited patients. Follicular helper T cells, measured by immune cell composition analysis, are significantly enriched in clinically benefited patients (p = 0.0373). Through time-course transcriptome analysis, in addition to several cytotoxic T-cell genes, MARCO on tumor-associated macrophages is found to be induced by ICI treatment in clinically benefited patients (p = 0.0040). Protein expression of these genes is confirmed by immunohistochemical and multiplex immunofluorescence analyses. To our knowledge, this is the first and largest genomic cohort study in Japanese patients with melanoma in which tumor samples were prospectively analyzed. Genomic and transcriptomic analyses reveal candidate biomarkers for ICI in Japan. Melanoma treatment has been improved by the introduction of drugs called Immune checkpoint inhibitors (ICIs). However, Japanese people often show lower response rates than white people. To understand why, we collected tumor and blood samples from Japanese people with melanoma and analyzed their DNA and RNA. DNA is a component of cells that is changed (mutated) compared to normal cells. We found that DNA from Japanese people tends to have fewer mutations that are associated with favorable responses to ICIs compared with DNA from white people. In contrast, certain features of the immune system could be used to predict which people would benefit from ICI treatment. Among them, we hypothesize that cells called “follicular helper T cells” and “MARCO-positive macrophages” may play particularly beneficial roles in Japanese patients. Kimura, Tanaka et al. perform exome and RNA sequencing in Japanese melanoma patients to investigate genomic and transcriptomic factors associated with clinical efficacy of immune checkpoint inhibitors. Findings reveal the characteristic genomic features and potential biomarkers of melanoma in Japanese patients.