Published online Apr 14, 2019. doi: 10.3748/wjg.v25.i14.1684
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
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.
G-NECs are highly malignant, clinically defiant, and lack of effective treatment. Recent research has proved the role of treatment targeting PD-1/PD-L1 pathway in several other advanced cancers. This study for the first time demonstrated that PD-L1 can be expressed by G-NEC cancer cells and the high PD-L1 expression was associated with a poor prognosis. These findings provide important implications for the potential use of antibody therapies targeting the PD-1/PD-L1 signaling pathway in G-NECs.
We performed this research to investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs.
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-NECs tissue specimens, while the copy number alterations of PD-L1 were assessed by qRT-PCR. Statistical analyses and graphical representations were performed using SPSS 22.0 software and GraphPad Prism 6 software, respectively. χ2 test and Fisher’s exact test were used to evaluate the correlation of PD-L1, PD-1, FOXP3, and CD8 with clinicopathologic parameters in patients with G-NECs. Survival curves were evaluated using the Kaplan-Meier method and differences were analyzed by the log-rank test. Identification of factors that had a significant influence on survival was performed by univariate and multivariate Cox regression analyses. Comparison between two groups was performed by the Student’s t-test or Mann–Whitney U test.
We found that 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. However, as a retrospective study, the small sample size of this research might result in some bias in the multivariable prognosis analysis, so larger sample studies are needed.
Our data demonstrated for the first time that the high expression of PD-L1 in G-NECs was 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.
By this study, we found that PD-1/PD-L1 pathway is involved in G-NECs. In the following, in vitro cell experiments and in vivo animal experiments are needed.