Serum concentrations of HGF are correlated with response to anti-PD-1 antibody therapy in patients with metastatic melanoma

• Published in: Journal of dermatological science 2019-01, Vol.93 (1), p.33-40
• Main Authors: Kubo, Yosuke, Fukushima, Satoshi, Inamori, Yukiko, Tsuruta, Mina, Egashira, Sho, Yamada-Kanazawa, Saori, Nakahara, Satoshi, Tokuzumi, Aki, Miyashita, Azusa, Aoi, Jun, Kajihara, Ikko, Tomita, Yusuke, Wakamatsu, Kazumasa, Jinnin, Masatoshi, Ihn, Hironobu
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; anti-PD-1 antibody therapy; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Biomarker; Biomarkers, Tumor - blood; c-Met inhibitor; Case-Control Studies; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cells, Cultured; Female; Follow-Up Studies; Healthy Volunteers; Hepatocyte Growth Factor - blood; Hepatocyte Growth Factor - metabolism; HGF; Humans; Leukocytes, Mononuclear; Male; Melanoma; Melanoma - blood; Melanoma - drug therapy; Melanoma - mortality; Melanoma - pathology; Middle Aged; Nivolumab - pharmacology; Nivolumab - therapeutic use; Perforin - metabolism; Primary Cell Culture; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Progression-Free Survival; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - metabolism; Skin Neoplasms - blood; Skin Neoplasms - drug therapy; Skin Neoplasms - mortality; Skin Neoplasms - pathology
• ISSN: 0923-1811; 1873-569X
• DOI: 10.1016/j.jdermsci.2018.10.001

Anti-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). To evaluate whether the serum concentration of HGF can be used as a biomarker for the clinical response to anti-PD-1 antibody therapy. This 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. Among 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. HGF 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.