Role of programmed death ligands in effective T-cell interactions in extranodal natural killer/T-cell lymphoma

Extranodal natural killer/T-cell lymphoma (ENKL) is marked by a profound cellular immune deficiency that may influence the capacity of T cells to extract an efficient antitumor immune response. It has been confirmed that the B7-CD28 pathway may promote tumor immune evasion by providing a negative regulatory signal. The current study analyzed the expression of programmed death 1 (PD-1)/programmed death ligand (PD-L) in ENKL cell lines and tissues. The functional studies were performed to analyze the functional activity of PD-L1 interacting with effective T cells in ENKL. PD-L1 and PD-L2 mRNA levels in ENKL cell lines were markedly upregulated compared with those in normal natural killer cells. The proteins constitutively expressed in the 30 ENKL specimens were significantly higher than in the 20 rhinitis specimens. In addition, PD-L1 and PD-L2 expression were found to closely correlate with certain clinical histopathological parameters. Furthermore, the count of PD-1⁺ tumor-infiltrating T lymphocytes was found to negatively correlate with the expression of PD-L1 and PD-L2. The PD-1 expression in the CD4⁺ and CD8⁺ T-cell subsets of 20 ENKL patients prior to therapy were significantly higher than that of the 10 healthy volunteers. In the functional studies, the cytokines (interleukin-2 and interferon-γ) secreted by CD8⁺ T cells were inhibited by PD-L1 expression in SNK-6 cells and this was restored with the presence of the PD-L1 blocking antibody. However no direct effect of PD-L1 was identified on CD8⁺ T-cell apoptosis and CD8⁺ T-cell cytotoxicity, as assessed by the proliferation of SNK-6 cells in the presence or absence of the neutralizing anti-PD-L1 antibody. The results of the current study revealed that PD-Ls and PD-1 are aberrantly expressed in ENKL and, furthermore, PD-L1 expression in SNK-6 cells was found to inhibit the activity of CD8⁺ T-cell cytokine secretion. This indicated that the PD-Ls may prevent effective antitumor immunity in vivo by interacting with tumor T cells, which provides important evidence to delineate the cellular immune deficiency mechanism in ENKL. Therefore, PD-1/PD-Ls are predicted to become novel targets for ENKL immunotherapy.