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Clinical Significance and Therapeutic Potential of the Programmed Death-1 Ligand/Programmed Death-1 Pathway in Human Pancreatic Cancer

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

Requests for reprints: Masayuki Sho, Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, 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 programmed death-1 ligand/programmed death-1 (PD-L/PD-1) pathway has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In this study, we tried to reveal the clinical importance and therapeutic potential of the PD-L/PD-1 pathway in pancreatic cancer, which is one of the most aggressive and intractable malignant tumors.

Experimental Design: We used immunohistochemistry to investigate PD-L expression in 51 patients with pancreatic cancer who underwent surgery and explored the therapeutic efficacy of blocking the PD-L1/PD-1 pathway in murine pancreatic cancer in vivo.

Results: PD-L1–positive patients had a significantly poorer prognosis than the PD-L1–negative patients, whereas there was no significant correlation of tumor PD-L2 expression with patient survival. PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, particularly CD8⁺ T cells. These clinical data have suggested that the PD-L1/PD-1 pathway may be a critical regulator in human pancreatic cancer. Monoclonal antibodies against PD-L1 or PD-1 induced a substantial antitumor effect on murine pancreatic cancer in vivo. PD-L1 blockade promoted CD8⁺ T-cell infiltration into the tumor and induced local immune activation. Furthermore, the combination of anti–PD-L1 monoclonal antibody and gemcitabine exhibited a significant synergistic effect on murine pancreatic cancer and resulted in complete response without overt toxicity.

Conclusion: Our data suggest for the first time that PD-L1 status may be a new predictor of prognosis for patients with pancreatic cancer and provide the rationale for developing a novel therapy of targeting the PD-L/PD-1 pathway against this fatal disease.

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