J Cancer 2021; 12(20):6126-6134. doi:10.7150/jca.55971 This issue

Research Paper

Programmed Cell Death Protein 1/Programmed Cell Death Ligand-1 Axis activates Intracellular ERK Signaling in Tumor Cells to Mediate Poor Prognosis in T-cell Lymphoma

Yang Li1*, Yue Fei1*, Lu Liu1*, Zheng Song1*, Xiangrui Meng1*, Lihua Qiu1, Lanfang Li1, Zhengzi Qian1, Shiyong Zhou1, Xiubao Ren2, Chengfeng Bi3, Bin Meng4, Huilai Zhang1✉, Xianhuo Wang1✉, Kai Fu3✉

1. Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China.
2. Department of Immunology/Biotherapy and Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China.
3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
4. Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China.
*These authors contributed equally to this paper.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Li Y, Fei Y, Liu L, Song Z, Meng X, Qiu L, Li L, Qian Z, Zhou S, Ren X, Bi C, Meng B, Zhang H, Wang X, Fu K. Programmed Cell Death Protein 1/Programmed Cell Death Ligand-1 Axis activates Intracellular ERK Signaling in Tumor Cells to Mediate Poor Prognosis in T-cell Lymphoma. J Cancer 2021; 12(20):6126-6134. doi:10.7150/jca.55971. Available from https://www.jcancer.org/v12p6126.htm

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Abstract

Graphic abstract

Purpose: To investigate the prognostic significance of programmed cell death ligand-1 (PD-L1) and phosphorylated ERK (p-ERK) and their interactions in T-cell lymphoma (TCL).

Methods: The mRNA levels of PD-L1 and ERK in TCL samples were analyzed. Formalin-fixed paraffin-embedded tissues from 69 TCL patients were collected to detect the expression of PD-L1 and p-ERK by multiplexed immunofluorescence staining. The total PD-L1 and p-ERK was measured by western blotting, and membrane PD-L1 was determined using flow cytometry.

Results: PD-L1 and ERK mRNA levels were significantly upregulated in TCL. The expression rates of PD-L1 and p-ERK were 52.2% and 27.5%, respectively. PD-L1 expression correlated with stage (R=0.304, P=0.011) and IPI score (R=0.313, P=0.009), and p-ERK expression correlated with stage (R=0.330, P=0.006) and IPI score (R=0.376, P=0.002). PD-L1 expression positively correlated with p-ERK expression (R=0.355, P=0.003). Patients with co-expression of PD-L1 and p-ERK had the worst overall survival (P=0.007). In three TCL cell lines with PD-L1 expression, we demonstrated that the expression of p-ERK was upregulated after stimulation with PD-1, suggesting that ERK signaling was activated.

Conclusions: The PD-1/PD-L1 axis activates intracellular ERK signaling in tumor cells and that PD-L1, p-ERK or their combination are potential biomarkers for predicting the prognosis in TCL patients.

Keywords: PD-L1, p-ERK, prognosis, T-cell lymphoma