Mechanism of action of PD-1 receptor/ligand targeted cancer immunotherapy.
Mechanism of action of PD-1 receptor/ligand targeted cancer immunotherapy.
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PD-1受体/配体靶向癌症免疫疗法的作用机制。
DOI：
10.1002/eji.202048994
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发表时间：
2021-08
影响因子：
5.4
通讯作者：
Ossendorp F
中科院分区：
文献类型：
--
作者：
Borst J;Busselaar J;Bosma DMT;Ossendorp F
靶向程序性死亡（PD-1）受体/配体（L）“检查点”的免疫疗法在许多癌症类型的治疗中迅速普及。为了增加治疗范围和疗效，需要预测性生物标志物和合理选择联合治疗。为了满足这些需求，我们必须详细了解PD-1的功能。我们在这里概述了最近对PD-1调节CD 8 + T细胞应答的见解。流行的观点是阻断PD-1/配体（L）相互作用“重振”在肿瘤微环境（TME）中功能失调的细胞毒性T淋巴细胞（CTL）。然而，这篇综述强调，肿瘤持续与相邻的引流淋巴结（LN）通信，并且PD-1检查点也在T细胞引发期间起作用。我们阐明了PD‐（L）1系统在T细胞/DC界面的作用，在那里它调节T细胞受体（TCR）信号传导和CD 28共刺激，从而控制肿瘤特异性T细胞的活化。我们还强调了CD 4 + T细胞在引发过程中的重要性，这使得DC能够提供最佳CTL分化所需的其他共刺激和细胞因子信号，并可能避免功能障碍状态。因此，我们提出PD-（L）1阻断应该利用LN功能并与“帮助”信号组合以优化CTL功效。对T细胞引发期间耗竭和PD-1信号传导的新见解挑战了PD-（L）1靶向治疗机制的经典观点。本文综述了抗PD-（L）1应答性T细胞的最新研究结果，如分化状态、位置和分子相互作用，并将其整合到PD-（L）1阻断效应的综合模型中。
Immunotherapy targeting the Programmed Death (PD‐1) receptor/ligand (L) “checkpoint” rapidly gains ground in the treatment of many cancer types. To increase treatment scope and efficacy, predictive biomarkers and rational selection of co‐treatments are required. To meet these demands, we must understand PD‐1 function in detail. We here outline recent insights into the regulation of the CD8+ T cell response by PD‐1. The prevailing view has been that blockade of PD‐1/ligand (L) interaction “reinvigorates” cytotoxic T lymphocytes (CTL) that were rendered dysfunctional in the tumor microenvironment (TME). However, this review stresses that tumors continuously communicate with adjacent draining lymph nodes (LNs) and that the PD‐1 checkpoint also operates during T cell priming. We clarify the role of the PD‐(L)1 system at the T cell/DC interface, where it regulates T cell receptor (TCR) signaling and CD28 costimulation and thus controls activation of tumor‐specific T cells. We also highlight the importance of CD4+ T cell help during priming, which allows DCs to provide other costimulatory and cytokine signals required for optimal CTL differentiation and likely avoidance of a dysfunctional state. Therefore, we pose that PD‐(L)1 blockade should exploit LN function and be combined with “help” signals to optimize CTL efficacy. Novel insights into exhaustion and PD‐1 signaling during T‐cell priming have challenged the classical view on the mechanisms underlying PD‐(L)1‐targeted therapy. This review integrates the latest findings on anti‐PD‐(L)1 responsive T cells, such as differentiation state, location, and molecular interactions, into a comprehensive model of PD‐(L)1 blockade effects in cancer.
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影响因子：
82.9
作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
64.5
作者：
Eickhoff S;Brewitz A;Gerner MY;Klauschen F;Komander K;Hemmi H;Garbi N;Kaisho T;Germain RN;Kastenmüller W
通讯作者：
Kastenmüller W
影响因子：
8
作者：
Fransen, Marieke F.;Schoonderwoerd, Mark;Ossendorp, Ferry
通讯作者：
Ossendorp, Ferry
影响因子：
16.6
作者：
Ahrends, Tomasz;Busselaar, Julia;Borst, Jannie
通讯作者：
Borst, Jannie
影响因子：
11.2
作者：
Ahrends, Tomasz;Babala, Nikolina;Borst, Jannie
通讯作者：
Borst, Jannie