%0 Journal Article
%T LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity.
%A Andrews LP
%A Butler SC
%A Cui J
%A Cillo AR
%A Cardello C
%A Liu C
%A Brunazzi EA
%A Baessler A
%A Xie B
%A Kunning SR
%A Ngiow SF
%A Huang YJ
%A Manne S
%A Sharpe AH
%A Delgoffe GM
%A Wherry EJ
%A Kirkwood JM
%A Bruno TC
%A Workman CJ
%A Vignali DAA
%J Cell
%V 187
%N 16
%D 2024 Aug 8
%M 39121848
%F 66.85
%R 10.1016/j.cell.2024.07.016
%X 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.