Co-expression of PD-L1 and p-AKT is associated with poor prognosis in diffuse large B-cell lymphoma via PD-1/PD-L1 axis activating intracellular AKT/mTOR pathway in tumor cells

// Ling Dong 1, * , Huijuan Lv 1, * , Wei Li 1 , Zheng Song 1 , Lanfang Li 1 , Shiyong Zhou 1 , Lihua Qiu 1 , Zhengzi Qian 1 , Xianming Liu 1 , Lixia Feng 1 , Bin Meng 2 , Kai Fu 1, 3 , Xi Wang 4 , Qiang Pan-Hammarström 1, 5 , Ping Wang 6 , Xianhuo Wang 1 , Huilai Zhang 1 1 Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China 2 Department of Pathology, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China 3 Department of Pathology and Microbiology and Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA 4 Department of Cellular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China 5 Department of Laboratory Medicine, Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden 6 Department of Radiotherapy, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China * These authors have contributed equally to this work Correspondence to: Huilai Zhang, email: zhlwgq@126.com Xianhuo Wang, email: tjzlyy_xianhuow@163.com Keywords: PD-1, PD-L1, p-AKT, AKT/mTOR signaling, DLBCL Received: January 06, 2016     Accepted: March 31, 2016     Published: April 27, 2016 ABSTRACT Programmed death-1 (PD-1) /programmed death-ligand 1 (PD-L1) engagement usually leads to diminished antitumor T-cell responses, which mediates the immune escape of tumor cells. However, little is known whether PD-1/PD-L1 could directly activates intracellular oncogenic signaling pathways in tumor cells. The purpose of this study is to investigate whether intracellular AKT/mTOR signaling could be directly activated by PD-1/PD-L1 during the malignant progression in diffuse large B-cell lymphoma (DLBCL). Detection of the expression of PD-L1 and p-AKT by immunohistochemistry (IHC) showed that both proteins were overexpressed in 54% and 48% DLBCL cases, respectively. Spearman test showed that PD-L1 expression was correlated with p-AKT expression (R=0.244, χ 2 =5.962; P =0.017) and the expression of PD-L1 and p-AKT were also correlated with clinic-pathological characteristics. In addition, survival analysis showed that DLBCL patients who co-expressed PD-L1 and p-AKT had significantly poorer outcome than patients with single positive or both negative expression ( P <0.05). In vitro, total PD-L1 and membrane PD-L1 (mPD-L1) proteins were overexpressed in five DLBCL cell lines by western blot and flow cytometry. We observed that AKT/mTOR pathway was activated in DLBCL cells after stimulated with human recombination PD-1/Fc. Taken together, these results suggested that the combination of PD-1/PD-L1 antibodies and AKT/mTOR inhibitor might be a promising and novel therapeutic approach for DLBCL in the future.