美国匹兹堡大学医学院Dario A.A. Vignali团队发现，LAG-3和PD-1在CD8+ T细胞上协同作用以驱动T细胞衰竭并阻碍自身分泌IFN-γ依赖的抗肿瘤免疫。该项研究成果发表在2024年8月8日出版的《细胞》杂志上。
研究人员表示，克服对PD-1阻断的免疫介导的耐药性仍然是一个主要的临床挑战。联合使用nivolumab（抗PD-1）和relatlimab（抗LAG-3）的疗效在黑色素瘤患者中已得到增强，且这是首个获得FDA批准的此类联合治疗。然而，这两种抑制性受体如何协同作用以阻碍抗肿瘤免疫仍不清楚。
研究人员发现，缺乏PD-1和LAG-3的CD8+ T细胞与缺乏任一受体的CD8+ T细胞相比，在小鼠黑色素瘤模型中介导了增强的肿瘤清除和长期生存。缺乏PD-1和LAG-3的CD8+ T细胞在转录组上有所不同，具有广泛的TCR克隆性以及富集的效应型和干扰素响应基因，从而释放更多IFN-γ，显示其功能性。
LAG-3和PD-1共同驱动T细胞衰竭，在调节TOX表达方面发挥主导作用。在机制上，PD-1和LAG-3缺失的CD8+ T细胞增强抗肿瘤免疫需要自分泌的细胞内IFN-γ信号，为如何通过组合靶向LAG-3和PD-1提高疗效提供了见解。
附：英文原文
Title: LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity
Author: 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
Issue&Volume: 2024/08/08
Abstract: 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 FDAapproved. However, how these two inhibitory receptors synergize to hinder anti-tumorimmunity 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 survivalin mouse models of melanoma. PD-1- and LAG-3-deficient CD8+ T cells were transcriptionally distinct, with broad TCR clonality and enrichmentof effector-like and interferon-responsive genes, resulting in enhanced IFN-γ releaseindicative of functionality. LAG-3 and PD-1 combined to drive T cell exhaustion, playinga dominant role in modulating TOX expression. Mechanistically, autocrine, cell-intrinsicIFN-γ signaling was required for PD-1- and LAG-3-deficient CD8+ T cells to enhance anti-tumor immunity, providing insight into how combinatorialtargeting of LAG-3 and PD-1 enhances efficacy.
DOI: 10.1016/j.cell.2024.07.016
Source: https://www.cell.com/cell/abstract/S0092-8674(24)00776-1