• Yosuke Kubo, Satoshi Fukushima, Yukiko Inamori, Mina Tsuruta, Sho Egashira, Saori Yamada-Kanazawa, Satoshi Nakahara, Aki Tokuzumi, Azusa Miyashita, Jun Aoi, Ikko Kajihara, Yusuke Tomita, Kazumasa Wakamatsu, Masatoshi Jinnin, and Hironobu Ihn.
• Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan.
• J. Dermatol. Sci. 2019 Jan 1; 93 (1): 33-40.

BackgroundAnti-programmed cell death protein (PD)-1 antibody treatment is associated with a notable improvement in only 30%-40% of patients. Thus, a predictive and easily measured marker of the clinical benefit of anti-PD-1 antibody treatment is necessary; therefore, in this study, we focused on the serum concentration of hepatocyte growth factor (HGF).ObjectivesTo evaluate whether the serum concentration of HGF can be used as a biomarker for the clinical response to anti-PD-1 antibody therapy.MethodsThis study included 29 metastatic melanoma patients receiving nivolumab or pembrolizumab. Nine patients responded to anti-PD-1 antibody treatment, whereas the other 20 patients did not. The serum concentrations of HGF were analyzed by using ELISA. In 28 patients, immunohistochemical analysis of the HGF protein in patients' cancer tissues was also performed. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with an anti-CD3 antibody in the presence or absence of HGF and c-MET inhibitor. The expression of perforin in CD8+ T cells were evaluated by using flow cytometry.ResultsAmong the 29 recruited patients, the non-responders displayed higher serum concentrations of HGF than the responders (P =  0.00124). Patients with low serum concentrations of HGF showed longer overall survival (N = 28, P =  0.039; HR 0.3125, 95% CI 0.1036-0.9427) and progression-free survival (N = 24, P =  0.0068; HR 0.2087, 95% CI 0.06525-0.6676) than those with high concentrations of HGF. We observed a significant correlation between the serum concentration of HGF and immunohistochemical-positive staining (P =  0.000663). In a flow cytometry analysis of PBMCs from healthy donors, HGF was found to downregulate perforin secretion. Furthermore, the addition of capmatinib, a specific inhibitor of c-MET, increased the expression of perforin in CD8+ T cells.ConclusionsHGF concentration represents a valid biomarker that can be further developed for the evaluation of anti-PD-1 therapy. Our results suggested that c-MET inhibition promotes perforin expression in CD8+ T cells. Therefore, c-MET inhibitors can activate the immune system and may play an important role in combined immunotherapy.Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

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