LAG-3 和 PD-1 与 CD8 T 细胞协同作用，导致 T 细胞耗竭并阻碍自分泌 IFN-γ 依赖性抗肿瘤免疫。
LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity.
发表日期：2024 Aug 08
作者：
Lawrence P Andrews, Samuel C Butler, Jian Cui, Anthony R Cillo, Carly Cardello, Chang Liu, Erin A Brunazzi, Andrew Baessler, Bingxian Xie, Sheryl R Kunning, Shin Foong Ngiow, Yinghui Jane Huang, Sasikanth Manne, Arlene H Sharpe, Greg M Delgoffe, E John Wherry, John M Kirkwood, Tulia C Bruno, Creg J Workman, Dario A A Vignali
来源：
CELL
摘要：
克服免疫介导的 PD-1 阻断耐药性仍然是一项重大的临床挑战。在黑色素瘤患者中，纳武单抗（抗 PD-1）和 relatlimab（抗 LAG-3）联合治疗的疗效得到了增强，这是此类药物中首个获得 FDA 批准的药物。然而，这两种抑制性受体如何协同作用阻碍抗肿瘤免疫仍不清楚。在这里，我们发现，与缺乏任一受体的 CD8 T 细胞相比，同时缺乏 PD-1 和 LAG-3 的 CD8 T 细胞可介导黑色素瘤小鼠模型中肿瘤清除率的增强和长期存活。 PD-1 和 LAG-3 缺陷的 CD8 T 细胞在转录上是不同的，具有广泛的 TCR 克隆性以及效应子样和干扰素响应基因的富集，导致 IFN-γ 释放增强（表明功能）。 LAG-3 和 PD-1 结合可驱动 T 细胞耗竭，在调节 TOX 表达中发挥主导作用。从机制上讲，PD-1 和 LAG-3 缺陷的 CD8 T 细胞需要自分泌、细胞固有的 IFN-γ 信号传导来增强抗肿瘤免疫，从而深入了解 LAG-3 和 PD-1 的组合靶向如何增强疗效.版权所有 © 2024 Elsevier Inc. 保留所有权利。
Overcoming immune-mediated resistance to PD-1 blockade remains a major clinical challenge. Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) treatment, the first in its class to be FDA approved. However, how these two inhibitory receptors synergize to hinder anti-tumor immunity remains unknown. Here, we show that CD8+ T cells deficient in both PD-1 and LAG-3, in contrast to CD8+ T cells lacking either receptor, mediate enhanced tumor clearance and long-term survival in mouse models of melanoma. PD-1- and LAG-3-deficient CD8+ T cells were transcriptionally distinct, with broad TCR clonality and enrichment of effector-like and interferon-responsive genes, resulting in enhanced IFN-γ release indicative of functionality. LAG-3 and PD-1 combined to drive T cell exhaustion, playing a dominant role in modulating TOX expression. Mechanistically, autocrine, cell-intrinsic IFN-γ signaling was required for PD-1- and LAG-3-deficient CD8+ T cells to enhance anti-tumor immunity, providing insight into how combinatorial targeting of LAG-3 and PD-1 enhances efficacy.Copyright © 2024 Elsevier Inc. All rights reserved.