Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas

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.

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.

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.

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.

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.