Over-activated PD-1/PD-L1 axis facilitates the chemoresistance of diffuse large B-cell lymphoma cells to the CHOP regimen

Liu,Juan; Quan,Lina; Zhang,Chunhui; Liu,Aichun; Tong,Dongxia; Wang,Jinghua

doi:10.3892/ol.2017.7682

Over-activated PD-1/PD-L1 axis facilitates the chemoresistance of diffuse large B-cell lymphoma cells to the CHOP regimen

Authors:
- Juan Liu
- Lina Quan
- Chunhui Zhang
- Aichun Liu
- Dongxia Tong
- Jinghua Wang
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Affiliations: Department of Hematology, Harbin Medical University Second Hospital, Harbin, Heilongjiang 150086, P.R. China, Department of Hematology and Lymphology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150086, P.R. China, Department of Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150086, P.R. China, Department of Hematology, Harbin Medical University First Hospital, Harbin, Heilongjiang 150086, P.R. China
Published online on: December 21, 2017 https://doi.org/10.3892/ol.2017.7682
Pages: 3321-3328

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Abstract

Interaction between the programmed cell death ligand 1 (PD‑L1) and programmed cell death 1 (PD‑1) contributes to tumor cell resistance to chemotherapeutic agents. PD‑L1 is expressed in the cells of diffuse large B‑cell lymphoma (DLBCL), one common type of malignant non‑Hodgkin lymphomas. However, little is known about how the PD‑1/PD‑L1 pathway functions in the pathogenesis of DLBCL. Therefore, the present study investigated whether and how the PD‑1/PD‑L1 axis is involved in regulating the sensitivity of CRL2631, a DLBCL cell line, to the CHOP (Cyclophosphamide, Hydroxydaunorubicin/adriamycin, Oncovin/vincristine and Prednisone) chemotherapeutic regimen. CHOP treatment significantly decreased cell survival rate and increased apoptosis in CRL2631 cells. The application of recombinant human PD‑1 (rPD‑1) significantly decreased the cytotoxic effects of the CHOP regimen in CRL2631 cells, but not in the CRL2631 cells with PD‑L1 deficiency. In the CRL2631 cells, rPD‑1 enhanced the activity of the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt1) pathway. However, the activity level of the PI3K/Akt1 pathway was decreased in CHOP‑treated CRL2631 cells. The selective PI3K inhibitor BKM120 significantly increased CHOP‑induced apoptosis, but this effect was abolished by rPD‑1 and aggravated by PD‑L1 knockdown. In CHOP‑treated PD‑L1 knockdown cells, the increased apoptosis was markedly inhibited by the overexpression of constitutively active Akt1. Overall, the results demonstrate that the over‑activated PD‑1/PD‑L1 axis is associated with chemotherapeutic resistance of DLBCL cells to the CHOP regimen, potentially through a PI3K‑dependent mechanism.

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