Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer
Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer
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DOI：
10.1158/1078-0432.ccr-06-2746
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发表时间：
2007-04-01
影响因子：
11.5
通讯作者：
Nakajima, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Nomi, Takeo;Sho, Masayuki;Nakajima, Yoshiyuki
目的：最近发现程序性死亡-1配体/程序性死亡-1(PD-L/PD-1)通路在肿瘤免疫逃避宿主免疫系统中起关键作用。本研究试图揭示PD-L/PD-1通路在胰腺癌这一最具侵袭性和顽固性的恶性肿瘤中的临床意义和治疗潜力。实验设计：采用免疫组织化学方法检测51例胰腺癌手术患者中PD-L的表达，并探讨阻断PD-L1/PD-1通路对小鼠胰腺癌的治疗作用。结果：PD-L1阳性患者的预后明显低于PD-L1阴性患者，而肿瘤PD-L2的表达与患者生存期无明显相关性。PD-L1的表达与肿瘤浸润性T细胞，尤其是CD8(+)T细胞呈负相关。这些临床数据表明，PD-L1/PD-1通路可能是人胰腺癌的关键调节因子。抗PD-L1或PD-1的单抗在体内对小鼠胰腺癌有显著的抗肿瘤作用。PD-L1阻断可促进CD8(+)T细胞向肿瘤的侵袭，并诱导局部免疫激活。此外，抗PD-L1单抗联合吉西他滨对小鼠胰腺癌有显著的协同作用，且完全有效，且无明显毒性。结论：首次提示PD-L1状态可能成为预测胰腺癌患者预后的新指标，并为开发针对PD-L/PD-1通路的新的治疗方法提供了理论依据。
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.