靶向免疫检查点抑制剂程序性细胞死亡蛋白1（PD-1）的治疗性单克隆抗体（mAb）通过缓解T细胞耗竭在抗癌治疗中取得了显著的临床成功。阻断PD-1与其配体PD-L1和PD-L2的相互作用是促进耗竭的T细胞功能恢复的重要决定因素。在这里，我们展示了抗PD-1 mAb通过另一种机制作用，导致记忆性CD4＋和CD8＋ T细胞表面PD-1表达的下调。PD-1受体的下调是与受体内吞不同的过程，并且以CD14＋单核细胞依赖的方式进行，其中CD64/Fcγ受体I作为这种T细胞外源性过程的主要因素。重要的是，PD-1表面的下调极大增强了PD-1＋CD8＋ T细胞的特异性抗原功能恢复。我们的研究展示了减少PD-1细胞表面水平并限制PD-L1/2的抑制性靶向的新机制，从而增强了抗PD-1抗体恢复T细胞功能的疗效。 版权所有©2023 Joo, Petrovas, de Leval, Noto, Obeid, Fenwick and Pantaleo

Therapeutic monoclonal antibodies (mAb) targeting the immune checkpoint inhibitor programmed cell death protein 1 (PD-1) have achieved considerable clinical success in anti-cancer therapy through relieving T cell exhaustion. Blockade of PD-1 interaction with its ligands PD-L1 and PD-L2 is an important determinant in promoting the functional recovery of exhausted T cells. Here, we show that anti-PD-1 mAbs act through an alternative mechanism leading to the downregulation of PD-1 surface expression on memory CD4+ and CD8+ T cells. PD-1 receptor downregulation is a distinct process from receptor endocytosis and occurs in a CD14+ monocyte dependent manner with the CD64/Fcγ receptor I acting as the primary factor for this T cell extrinsic process. Importantly, downregulation of surface PD-1 strongly enhances antigen-specific functional recovery of exhausted PD-1+CD8+ T cells. Our study demonstrates a novel mechanism for reducing cell surface levels of PD-1 and limiting the inhibitory targeting by PD-L1/2 and thereby enhancing the efficacy of anti-PD-1 Ab in restoring T cell functionality.Copyright © 2023 Joo, Petrovas, de Leval, Noto, Obeid, Fenwick and Pantaleo.