Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts.
Cancer Immunol Res. 2021 Dec;9(12):1465-1475. doi: 10.1158/2326-6066.CIR-21-0493. Epub 2021 Oct 11.
PD-1 expression marks activated T cells susceptible to PD-1-mediated inhibition but not whether a PD-1-mediated signal is being delivered. Molecular predictors of response to PD-1 immune checkpoint blockade (ICB) are needed. We describe a monoclonal antibody (mAb) that detects PD-1 signaling through the detection of phosphorylation of the immunotyrosine switch motif (ITSM) in the intracellular tail of mouse and human PD-1 (phospho-PD-1). We showed PD-1 tumor-infiltrating lymphocytes (TILs) in MC38 murine tumors had high phosphorylated PD-1, particularly in PD-1TIM-3 TILs. Upon PD-1 blockade, PD-1 phosphorylation was decreased in CD8 TILs. Phospho-PD-1 increased in T cells from healthy human donors after PD-1 engagement and decreased in patients with Hodgkin lymphoma following ICB. These data demonstrate that phosphorylation of the ITSM motif of PD-1 marks dysfunctional T cells that may be rescued with PD-1 blockade. Detection of phospho-PD-1 in TILs is a potential biomarker for PD-1 immunotherapy responses.
PD-1 表达标志着激活的 T 细胞易受 PD-1 介导的抑制作用影响，但不能确定 PD-1 介导的信号是否正在传递。需要寻找预测 PD-1 免疫检查点阻断（ICB）反应的分子标志物。我们描述了一种单克隆抗体（mAb），它通过检测小鼠和人 PD-1 胞内尾部免疫酪氨酸开关基序（ITSM）的磷酸化来检测 PD-1 信号（磷酸化 PD-1）。我们在 MC38 鼠肿瘤中发现 PD-1 肿瘤浸润淋巴细胞（TIL）有高磷酸化的 PD-1，特别是在 PD-1TIM-3 TIL 中。在 PD-1 阻断后，CD8 TIL 中的 PD-1 磷酸化减少。在 PD-1 结合后，来自健康供体的 T 细胞中磷酸化 PD-1 增加，而在接受 ICB 治疗的霍奇金淋巴瘤患者中则减少。这些数据表明，PD-1 的 ITSM 基序磷酸化标志着功能失调的 T 细胞，这些细胞可能通过 PD-1 阻断得到挽救。在 TIL 中检测磷酸化 PD-1 可能是 PD-1 免疫治疗反应的潜在生物标志物。
