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.

To evaluate whether angiogenic factors are of clinical relevance to actual human pancreatic cancers, we studied the intratumoral microvessel density (IMD), and PD-ECGF, VEGF protein expression in 40 pancreatic cancers using immunohistochemistry. We also investigated PD-ECGF and VEGF gene expression using reverse transcriptase-PCR (RT-PCR). Of the 40 pancreatic cancers studied, 30 carcinomas (75.0%) were evaluated to be PD-ECGF -positive and 10 carcinomas (25.0%) were determined to be PD-ECGF -negative. In contrast, 27 carcinomas (67.5%) were evaluated to be VEGF -positive, whereas 13 carcinomas (32.5%) were VEGF -negative. VEGF gene expression was moderately associated with an increase in the IMD ( r 2 = 0.181, P = 0.006), but no significant relationship was found between PD-ECGF gene expression and the IMD ( r 2 = 0.093, P = 0.059). However, tumours with positive expression for both PD-ECGF and VEGF had a higher IMD ( P = 0.027). The results of the immunohistochemistry agreed well with the results of the quantitative RT-PCR. The median survival time of the hypervascular group was significantly shorter than that of the hypovascular group ( P < 0.0001). In comparing the survival according to PD-ECGF and VEGF gene expression, the median survival time of the patients with positive PD-ECGF expression was significantly shorter than those with negative PD-ECGF expression ( P = 0.040). Furthermore, the median survival time of the patients with positive VEGF expression was significantly shorter than those with negative VEGF expression ( P = 0.048). However, the Cox multivariate analysis indicated that the IMD and VEGF expression were independent prognostic factors of the various clinicopathologic variables in pancreatic cancer patients ( P = 0.0021 and P = 0.0443, respectively). © 1999 Cancer Research Campaign

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Purpose: RECK, a membrane-anchored regulator of matrix metalloproteinases (MMPs), is widely expressed in healthy tissue, whereas it is expressed at lower levels in many tumor-derived cell lines. Studies in mice and cultured cells have shown that restoration of RECK expression inhibits tumor invasion, metastasis, and angiogenesis. However, the clinical relevance of these findings remains to be fully documented. Here we examined the expression of RECK and one of its targets, MMP-9, in colorectal cancer tissue.Experimental Design: The RECK and MMP-9 expression levels in colorectal cancer samples from 53 patients were determined by immunohistochemical techniques. The expression level of each protein was scored, and the patients were divided into two groups based on these scores. In 33 cases, we performed gelatin zymography to estimate the degree of MMP-2 and MMP-9 activation. Microvessel density and vascular endothelial growth factor (VEGF) expression were also evaluated histologically.Results: RECK protein was detected in 30 of 53 (56.6%) specimens. Importantly, patients with tumors expressing relatively high levels of RECK (high-RECK group) had a significantly lower risk of recurrence than did patients with tumors expressing relatively low levels of RECK (low-RECK group; P ‫؍‬ 0.011). Moreover, RECK-dominant (RECK score > MMP-9 score) patients showed a significantly lower incidence of recurrence than did MMP-9-dominant patients (P ‫؍‬ 0.0003). Multivariate analysis revealed that the RECK/MMP-9 balance was an independent prognostic factor (P ‫؍‬ 0.0122). The expression of VEGF and microvessel density were inversely correlated with the level of RECK expression.Conclusions: RECK/MMP-9-balance is an informative prognostic indicator for colorectal cancer. Our data also suggest that RECK suppresses tumor angiogenesis, probably by limiting the availability of VEGF in tumor tissues.