{Reference Type}: Journal Article
{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}: Andrews LP;Butler SC;Cui J;Cillo AR;Cardello C;Liu C;Brunazzi EA;Baessler A;Xie B;Kunning SR;Ngiow SF;Huang YJ;Manne S;Sharpe AH;Delgoffe GM;Wherry EJ;Kirkwood JM;Bruno TC;Workman CJ;Vignali DAA;
{Journal}: Cell
{Volume}: 187
{Issue}: 16
{Year}: 2024 Aug 8
{Factor}: 66.85
{DOI}: 10.1016/j.cell.2024.07.016
{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.