Copyright
©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas
Min-Wei Yang, Xue-Liang Fu, Yong-Sheng Jiang, Xiao-Jing Chen, Ling-Ye Tao, Jian-Yu Yang, Yan-Miao Huo, Wei Liu, Jun-Feng Zhang, Pei-Feng Liu, Qiang Liu, Rong Hua, Zhi-Gang Zhang, Yong-Wei Sun, De-Jun Liu
Min-Wei Yang, Xue-Liang Fu, Yong-Sheng Jiang, Ling-Ye Tao, Jian-Yu Yang, Yan-Miao Huo, Wei Liu, Jun-Feng Zhang, Rong Hua, Yong-Wei Sun, De-Jun Liu, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Xiao-Jing Chen, Pei-Feng Liu, Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Qiang Liu, Department of Pathology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Zhi-Gang Zhang, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200240, China
Author contributions: Liu DJ and Sun YW conceived and designed the experiments; Yang MW, Fu XL, Jiang YS, and Chen XJ performed the experiments and wrote the manuscript; Fu XL and Yang MW analyzed the data; Tao LY, Yang JY, Huo YM, Liu W, Zhang JF, Liu PF, and Liu Q contributed clinical samples and data; Liu DJ, Sun YW, Zhang ZG, and Hua R revised and edited the manuscript; all authors reviewed and approved the final manuscript.
Supported by Municipal Commission of Health and Family Planning of Shanghai, China (No. 20174Y0243 to Liu DJ, No. 20154Y0163 to Chen XJ), Cultivating Funds of Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China (No. PYXJS 16-002 to Liu W).
Institutional review board statement: The research was approved by the Research Ethics Committee of Ren Ji Hospital.
Conflict-of-interest statement: No potential conflicts of interest are disclosed.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: De-Jun Liu, MAMS, Doctor, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No 160, Pujian Road, Shanghai 200127, China. liudj1126@yeah.net
Telephone: +86-21-68383773 Fax: +86-21-68383699
Received: January 30, 2019
Peer-review started: January 31, 2019
First decision: February 26, 2019
Revised: March 5, 2019
Accepted: March 16, 2019
Article in press: March 16, 2019
Published online: April 14, 2019
BACKGROUND
Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas (G-NECs) remains unknown.
AIM
To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant.
METHODS
We investigated the expression of PD-L1 on tumor cells and PD-1+, CD8+, and FOXP3+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR.
RESULTS
Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43 G-NECs, 21 (48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival (OS). The high expression of PD-L1 was correlated with abundant PD-1+ tumor infiltrating lymphocytes (TILs) instead of CD8+ TILs and FOXP3+ regulatory T cells (Tregs). Our analysis also suggested that the infiltration of CD8+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance (P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without.
CONCLUSION
Our data demonstrated for the first time that high expression of PD-L1 in G-NECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in G-NECs.
Core tip: This study for the first time demonstrated that programmed death ligand 1 (PD-L1) can be expressed by gastric neuroendocrine carcinoma (G-NEC) cancer cells and the high PD-L1 expression was associated with a poor prognosis. And the high expression of PD-L1 may be due to the copy number variation of PD-L1 gene or stimulation of tumor infiltrating lymphocytes. These findings provide important implications for the potential use of antibody therapies targeting the PD-1/PD-L1 signaling pathway in G-NECs.
