Clinical Significance of Programmed Death-1 Ligand-1 and Programmed Death-1 Ligand-2 Expression in Human Esophageal Cancer

Abstract

Purpose:The negative regulatory programmed death-1/programmed death-1ligand (PD-1/PD-L) pathway inT-cell activation has been suggested to play an important role in tumor evasion from host immunity. In this study, we investigated the expression of PD-L1 and PD-L2 in human esophageal cancer to define their clinical significance in patients'prognosis after surgery. Experimental Design: PD-L1 and PD-L2 gene expression was evaluated in 41esophagectomy patients by real-time quantitative PCR. The protein expression was also evaluated with newly generated monoclonal antibodies that recognize human PD-L1 (MIH1) and PD-L2 (MIH18). Results: The protein and the mRNA levels of determination by immunohistochemistry and realtime quantitative PCR were closely correlated. PD-L^positive patients had a significantly poorer prognosis than the negative patients. This was more pronounced in the advanced stage of tumor than in the early stage. Furthermore, multivariate analysis indicated that PD-L status was an independent prognostic factor. Although there was no significant correlation between PD-L1 expression and tumor-infiltrating T lymphocytes, PD-L2 expression was inversely correlated with tumor-infiltrating CD8 + Tcells. Conclusions:Thesedatasuggest thatPD-L1andPD-L2statusmaybeanewpredictorofprognosis for patients with esophageal cancer and provide the rationale for developing novel immunotherapy of targeting PD-1/PD-L pathway.

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“…PD-L1 engagement of PD-1 may be one mechanism whereby tumors evade immunosurveillance by directly limiting effector T-cell activity. Several studies support the notion that PD-L1 expression and, in some cases, PD-L2 expression is associated with tumor aggressiveness and adverse patient outcome (14,(20)(21)(22).…”

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

“…Some studies reported negative impact of PD-L1 and PD-L2 expression on patient survival in pancreatic cancer 31 and renal cell cancer 55 in addition to an inverse relationship with tumor infiltrating CD8 C lymphocytes in esophageal cancer. 43 However, others did not find a correlation with poor survival 32,33 and some showed an association with poor clinicopathological factors and increased immune cell infiltrate. 30 Thus, the prognostic relevance of PD-L1 and PD-L2 expression in tumors is still controversial.…”

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“…The finding that PD-L1 is commonly upregulated on many different tumor types including melanoma [47], ovarian cancer [48], lung cancer [49], clear cell renal carcinoma [50], urothelial carcinoma [51], squamous cell carcinomas of the head and neck [52,53], esophageal cancer [54], cervical cancer [55], breast carcinoma [56], pancreatic cancer [57], gastric cancer [58], Wilms tumor [59] and glioblastoma [60], and that PD-1 is expressed in TILs, has created an important rationale for mAb blockade of this pathway for cancer immunotherapy.…”