Search

Background. Programmed cell death ligand 1 (PD-L1) is a key inhibitor to the immune response by binding to the specific receptor PD-1. Adenosine receptor 2 (A2aR) can play an immunosuppressive role in tumor microenvironment by binding to its ligand adenosine (ADO). However, the expression of these two markers has been rarely studied in colorectal cancer simultaneously.Materials and Methods. We, respectively, collected tumor and adjacent nontumor tissue specimens of 204 patients with colorectal cancer. The expressions of PD-L1 and A2aR were detected by immunohistochemistry. The association among their expressions with clinicopathological characteristics and prognostic parameters were analyzed as well.Results. The expressions of PD-L1 and A2aR in tumor tissues were both higher than those in matched adjacent nontumor tissues. PD-L1 expression was significantly correlated with lymph node metastasis and tumor TNM stage. A2aR expression was significantly correlated with tumor size, depth of tumor invasion, and TNM stage. Univariate analysis showed that the high expressions of PD-L1 and A2aR were inversely correlated with the overall survival, respectively. Multivariate analysis further confirmed that both of them were independent prognostic markers for patients.Conclusion. The results of this study suggested that the high expressions of PD-L1 and A2aR were associated with a poor prognosis of colorectal cancer. Coinhibition of these two proteins may be a new breakthrough in the treatment of this disease.

Background. Adenosine, derived from the degradation of ATP via ectonucleotidases CD39 and CD73, is a critical immunosuppressive metabolite in the hypoxic microenvironment of tumor tissue. Adenosine signaling via A2aR can inhibit the antitumor immune response of CD8+T cells. CD39 and CD73 high-expressing Tregs play a critical role in tumor immune evasion of gastric cancer (GC). The present study investigated the underlying mechanism by which Tregs suppress antitumor immune responses in GC.Materials and Methods. Fifty-two GC samples were collected, and the frequency of FoxP3+Tregs and CD8+T cells and density ratios of A2aR+/CD8+T cells, CD39+/FoxP3+Tregs, and CD73+/FoxP3+Tregs in GC were assessed with multiplex immunofluorescence. The expression of FoxP3 and A2aR in GC tissues was also detected by the immunoblotting assay. We next investigated the relationship between density of FoxP3+Tregs, ratio of A2aR+/CD8+T cells, and clinicopathological parameters. At the same time, Tregs and CD8+T cells were isolated from peripheral blood of five GC patients, and the antagonists of CD39 and CD73 were used to assess the ability of Tregs to decompose ATP into adenosine. In addition, we cocultured CD8+T cells and Tregs with antagonists of A2aR and A2bR in order to examine the alterations in immune function of CD8+T cells.Results. The density of both FoxP3+Tregs and A2aR+/CD8+T cells was higher in GC tissue compared to peritumoral normal tissue and significantly correlated with the TNM stage, lymph node metastasis, and distant metastasis of GC. The process of Treg hydrolysis of ATP into adenosine was blocked by the antagonists of CD39 and CD73. In addition, Tregs could induce apoptosis and inhibit proliferation of CD8+T cells, while this effect could be obviously reduced by applying the antagonist of A2aR or A2aR+A2bR. Moreover, IFN-γ, TNF-α, and perforin generated by CD8+T cells could also be inhibited through the adenosine A2aR pathway.Conclusions. The FoxP3+Tregs and A2aR+/CD8+T cells were excessively infiltrated in GC tissue. Tregs from GC can decompose ATP to adenosine and in turn induce apoptosis and inhibit the proliferation of CD8+T cells through the A2aR pathway, further leading to immune escape of GC.