title: Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients.
abstract: Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4+T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8+T cells, and serum cytokine levels (IFNγ, IL-4, IL-9, IL-10, TGF-β) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-β compared to non-responders. Th9 induction by IL-4 and TGF-β was enhanced by PD-1/PD-L1 blockadein vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model.In vivoIL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8+T cells was enhanced in the presence of IL-9in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nonomura
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Otsuka
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto, Japan.
authors.forename: Chisa
authors.initials: C
authors.lastname: Nakashima
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto, Japan.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Seidel
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kitoh
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Dainichi
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto, Japan.
authors.forename: Saeko
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sawada
authors.affiliation: Department of Dermato-Oncology/Dermatology, National Hospital Organization Kagoshima Medical Center , Kagoshima, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Matsushita
authors.affiliation: Department of Dermato-Oncology/Dermatology, National Hospital Organization Kagoshima Medical Center , Kagoshima, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Division of Dermatology, Niigata Cancer Center Hospital , Niigata, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takenouchi
authors.affiliation: Department of Dermatology, Tohoku University Graduate School of Medicine , Sendai, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: Department of Dermatology, Toyama Prefectural Central Hospital , Toyama, Japan.
authors.forename: Naohito
authors.initials: N
authors.lastname: Hatta
authors.affiliation: Department of Dermatology, Tenri Hospital , Tenri, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Koreeda
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Honda
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Singapore Immunology Network (SIgN) and Institute of Medical Biology, Agency for Science, Technology and Research (ASTAR), Biopolis, Singapore.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
keywords: Anti-PD-1 antibody; Th9; melanoma; nivolumab