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

Background Immune checkpoint inhibitors (ICIs) have greatly improved the prognosis of advanced melanoma. However, the efficacy of ICIs in Japanese patients has been found to be lower than that in Caucasians. We aimed to elucidate the genomic and transcriptomic features associated with the response to ICIs in Japanese patients with melanoma. Patients and methods A total of 129 tumor samples from 78 patients with melanoma who received therapeutic regimens with or without ICI treatment were collected from 13 institutions in Japan. We performed exome and RNA sequencing and investigated the association between genomic and transcriptomic factors and the clinical efficacy of ICI therapy. Time-course data were also analyzed. This is the first and largest genomic cohort study in Japanese patients with melanoma in which tumor samples were prospectively analyzed. Results The number of somatic SNVs in Japanese patients with melanoma was lower than that in TCGA Caucasian data owing to the biased distribution of WHO subtypes. The driver subtypes BRAF , NRAS, and NF1 were less prevalent, but triple wildtype predominantly existed in the Japanese cohort. An exome-wide survey revealed no significant association of mutated genes with ICI response; however, transcriptomic analysis revealed inflammation-associated genes, including several chemokines and cytokines, that were highly expressed in responders. Follicular helper T cells, estimated by immune cell composition analysis, were significantly enriched in responders ( p = 0.0422). Through time-course transcriptome analysis, in addition to several cytotoxic T-cell genes, MARCO on tumor-associated macrophages was found to be induced by ICI treatment in responders ( p = 0.0040). Protein expression of these genes was confirmed by immunohistochemical and multiplex immunofluorescence analyses. Conclusions Prospective genomic and transcriptomic analyses revealed candidate biomarkers for ICI treatment in Japanese patients with melanoma.