PDF(Pubmed)
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 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.
摘要：
克服免疫介导的对PD-1阻断的抗性仍然是主要的临床挑战。在联合使用nivolumab（抗PD-1）和relatlimab（抗LAG-3）治疗的黑色素瘤患者中，已证明疗效增强。这是同类产品中第一个获得FDA批准的。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然未知。这里,我们显示，CD8+T细胞缺乏PD-1和LAG-3，与缺乏任一受体的CD8+T细胞相反，在黑色素瘤小鼠模型中介导增强的肿瘤清除和长期存活。PD-1-和LAG-3缺陷型CD8+T细胞在转录上不同，具有广泛的TCR克隆性和效应物样和干扰素反应基因的富集，导致增强的IFN-γ释放指示功能性。LAG-3和PD-1联合驱动T细胞耗尽，在调节TOX表达中起主导作用。机械上,自分泌,PD-1-和LAG-3-缺陷的CD8+T细胞需要细胞固有的IFN-γ信号传导来增强抗肿瘤免疫力，深入了解LAG-3和PD-1的组合靶向如何增强疗效。
