Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri.
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Cancer Immunol Res. 2017 Feb;5(2):106-117. doi: 10.1158/2326-6066.CIR-16-0391. Epub 2017 Jan 10.
Antibody blockade of programmed death-1 (PD-1) or its ligand, PD-L1, has led to unprecedented therapeutic responses in certain tumor-bearing individuals, but PD-L1 expression's prognostic value in stratifying cancer patients for such treatment remains unclear. Reports conflict on the significance of correlations between PD-L1 on tumor cells and positive clinical outcomes to PD-1/PD-L1 blockade. We investigated this issue using genomically related, clonal subsets from the same methylcholanthrene-induced sarcoma: a highly immunogenic subset that is spontaneously eliminated in vivo by adaptive immunity and a less immunogenic subset that forms tumors in immunocompetent mice, but is sensitive to PD-1/PD-L1 blockade therapy. Using CRISPR/Cas9-induced loss-of-function approaches and overexpression gain-of-function techniques, we confirmed that PD-L1 on tumor cells is key to promoting tumor escape. In addition, the capacity of PD-L1 to suppress antitumor responses was inversely proportional to tumor cell antigenicity. PD-L1 expression on host cells, particularly tumor-associated macrophages (TAM), was also important for tumor immune escape. We demonstrated that induction of PD-L1 on tumor cells was IFNγ-dependent and transient, but PD-L1 induction on TAMs was of greater magnitude, only partially IFNγ dependent, and was stable over time. Thus, PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape from immune control, indicating that total PD-L1 expression in the immediate tumor microenvironment may represent a more accurate biomarker for predicting response to PD-1/PD-L1 blockade therapy, compared with monitoring PD-L1 expression on tumor cells alone. Cancer Immunol Res; 5(2); 106-17. ©2017 AACR.
抗体阻断程序性死亡受体-1（PD-1）或其配体 PD-L1，在某些肿瘤患者中导致了前所未有的治疗反应，但 PD-L1 表达在为这种治疗分层癌症患者方面的预后价值仍不清楚。关于肿瘤细胞上的 PD-L1 与 PD-1/PD-L1 阻断的阳性临床结果之间的相关性的报告存在冲突。我们使用来自相同甲基胆蒽诱导肉瘤的基因相关克隆亚群来研究这个问题：一个高度免疫原性的亚群，通过适应性免疫在体内被自发消除，一个免疫原性较低的亚群，在免疫功能正常的小鼠中形成肿瘤，但对 PD-1/PD-L1 阻断治疗敏感。使用 CRISPR/Cas9 诱导的功能丧失方法和过表达功能获得技术，我们证实肿瘤细胞上的 PD-L1 是促进肿瘤逃逸的关键。此外，PD-L1 抑制抗肿瘤反应的能力与肿瘤细胞抗原性成反比。宿主细胞上的 PD-L1 表达，特别是肿瘤相关巨噬细胞（TAM），对于肿瘤免疫逃逸也很重要。我们证明肿瘤细胞上 PD-L1 的诱导依赖于 IFNγ 且是短暂的，但 TAMs 上 PD-L1 的诱导程度更大，仅部分依赖于 IFNγ，并且随着时间的推移是稳定的。因此，肿瘤细胞或宿主免疫细胞上的 PD-L1 表达都可能导致肿瘤逃避免疫控制，这表明直接肿瘤微环境中的总 PD-L1 表达可能比单独监测肿瘤细胞上的 PD-L1 表达更能准确预测对 PD-1/PD-L1 阻断治疗的反应。Cancer Immunol Res; 5(2); 106-17. ©2017 AACR.
