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

Authors' Affiliations: Departments of ¹ Surgery, ² Internal Medicine, and ³ Otorhinolaryngology, Nara Medical University School of Medicine, Nara, Japan; ⁴ Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University; and ⁵ Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Requests for reprints: Masayuki Sho, Department of Surgery, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara-city, Nara, 634-8522, Japan. Phone: 81-744-29-8863; Fax: 81-744-24-6866; E-mail: m-sho{at}naramed-u.ac.jp.

Purpose: The negative regulatory programmed death-1/programmed death-1 ligand (PD-1/PD-L) pathway in T-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 41 esophagectomy 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 real-time 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⁺ T cells.

Conclusions: These data suggest that PD-L1 and PD-L2 status may be a new predictor of prognosis for patients with esophageal cancer and provide the rationale for developing novel immunotherapy of targeting PD-1/PD-L pathway.

Key Words: PD-1 • B7-H1 • B7-DC • T cell • Prognosis

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