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, 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.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) accounting for approximately 30-40% of newly diagnosedNHL cases [1]
The purpose of this study is to investigate whether intracellular AKT/mTOR signaling could be directly activated by Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) during the malignant progression in diffuse large B-cell lymphoma (DLBCL)
Kiyasu et al have demonstrated that PD-L1 expression was associated with poor overall survival in DLBCL patients (P =0.0323) [39], which was consistent with our results in this study
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) accounting for approximately 30-40% of newly diagnosed. It is a group of highly heterogeneous diseases with variable clinical features and molecular genetic alterations [2]. DLBCL can be classified as GCB, ABC and primary mediastinal B-cell lymphoma (PMBL). ABC and PMBL subgroups are grouped as non-GCB DLBCL. Since the addition of the rituximab (R) to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), the prognosis of DLBCL has been greatly improved [4]. About 30~40% DLBCL patients still couldn’t benefit from R-CHOP and eventually develop relapsed/refractory disease [5]. Further studies are needed to investigate the underlying molecular mechanism of DLBCL and to develop novel therapeutic approaches for this disease
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