Frequency of elevated peripheral Th9 cells in metastatic melanoma patients receiving anti-PD-1 therapy
Yumi Nonomura, Atsushi Otsuka, Chisa Nakashima, Judith Seidel, Yasuo Yamamoto, Kenji Kabashima
Department of Dermatology, Kyoto University Graduate School of Medicine
Anti programmed cell death 1 (PD-1) antibody, nivolumab, is associated with a significant improvement in overall survival and progression-free survival, but only 20 to 40 % of patients experience long-term benefit. It is therefore great interest to find a parameter validated as a surrogate marker of response or survival benefit.
To address this issue, frequencies of CD4+ T cell subsets (regulatory T cells, T helper (Th) 1, 2, 9, 17 and 22 cells), CD8+ T cells and cytokine serum levels (interferon (IFN) -, interleukin (IL) -4, IL-9, IL-10, transforming growth factor (TGF) -) were assessed in 46 melanoma patients treated with nivolumab. Eighteen patients responded to nivolumab, while the other 28 patients did not. An early increase in Th9 cell frequency during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, responders displayed elevated serum concentrations of TGF- compared to non-responders. Th9 induction with IL-4 and TGF- was enhanced by the presence of anti PD-1 antibody in vitro.
The role of IL-9 in disease progression was further assessed using melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and cytotoxic ability of murine melanoma specific CD8+ T cells was enhanced in the presence of IL-9 in vitro.
These findings suggest that Th9 cells may play an important role in the successful treatment of melanoma patients with nivolumab.