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
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Ling Dong1,*, Huijuan Lv1,*, Wei Li1, Zheng Song1, Lanfang Li1, Shiyong Zhou1, Lihua Qiu1, Zhengzi Qian1, Xianming Liu1, Lixia Feng1, Bin Meng2, Kai Fu1,3, Xi Wang4, Qiang Pan-Hammarström1,5, Ping Wang6, Xianhuo Wang1, Huilai Zhang1
1Department 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
2Department 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
3Department of Pathology and Microbiology and Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
4Department of Cellular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
5Department of Laboratory Medicine, Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
6Department 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
Huilai Zhang, email: email@example.com
Xianhuo Wang, email: firstname.lastname@example.org
Keywords: PD-1, PD-L1, p-AKT, AKT/mTOR signaling, DLBCL
Received: January 06, 2016 Accepted: March 31, 2016 Published: April 27, 2016
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, χ2=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.
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