Anti-PD1 up-regulates PD-L1 expression and inhibits T-cell lymphoma progression: possible involvement of an IFN-γ-associated JAK-STAT pathway

Weili Xue,1,* Weiming Li,1,* Tiantian Zhang,2 Zhaoming Li,1 Yingjun Wang,1 Yajuan Qiu,1 Yuanyuan Wang,1 Changying Chen,1 Dongjun Fu,3 Mingzhi Zhang1 1Oncology Department, The First Affiliated Hospital of Zhengzhou University, Erqi District, Zhengzhou, Henan Province, China; 2Toni Stephenson Lymphoma Center, City of Hope, Duarte, CA, USA; 3New Drug Research and Development Center, School of Pharmaceutical Sciences of Zhengzhou University, Zhengzhou, Henan Province, China *These authors contributed equally to this work Purpose: NK/T-cell neoplasms are rare, highly aggressive, and insensitive to chemotherapy. These lymphomas have a poor prognosis, with patients being vulnerable to relapse. Hence, there is a need for alternative treatments. The purpose of this study is to investigate whether anti-PD1 takes effect on NK/T cell lymphoma.Methods: The expression of PD-L1 in NK/T cell lines was investigated by flow cytometry and by Western blot. In vivo, overall survival and median survival time of mice bearing an NK/T cell line tumor was assessed. Tumor-infiltrating T cells and monocyte-derived suppressor cells were evaluated by flow cytometry. Levels of PD-L1 and components of the JAK-STAT pathway were assessed in tumor tissues by immunohistochemistry.Results: NK/T cell lines had greater expression of PD-L1 than normal peripheral blood human NK cells. In vivo, anti-PD1 treatment improved overall survival and median survival time of mice bearing an NK/T cell line. Furthermore, anti-PD1 treatment increased levels of PD-L1. Cultured tumor-infiltrating lymphocytes from mice treated with anti-PD1 had greater levels of IFN-γ than cultured lymphocytes from untreated animals. Further, levels of JAK2 and STAT1 were greater in mice treated with anti-PD1.Conclusion: In vivo, anti-PD1 inhibited the progression of an NK/T-cell lymphoma and up-regulated PD-L1 expression. This up-regulation may be through the IFN-γ-associated JAK-STAT pathway. Keywords: PD-L1, anti-PD1, NK/T-cell lymphoma, immunotherapy, JAK-STAT, IFN-γ &nbsp