LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity

• Published in: Cell Vol. 187; no. 16; pp. 4355 - 4372.e22
• Main Authors: Andrews, Lawrence P., Butler, Samuel C., Cui, Jian, Cillo, Anthony R., Cardello, Carly, Liu, Chang, Brunazzi, Erin A., Baessler, Andrew, Xie, Bingxian, Kunning, Sheryl R., Ngiow, Shin Foong, Huang, Yinghui Jane, Manne, Sasikanth, Sharpe, Arlene H., Delgoffe, Greg M., Wherry, E. John, Kirkwood, John M., Bruno, Tullia C., Workman, Creg J., Vignali, Dario A.A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.08.2024
• Subjects: Animals; anti-LAG-3; anti-PD-1; anti-tumor immunity; Antigens, CD - metabolism; Autocrine Communication; CD8+ T cell; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Female; Humans; IFN-γ; immune checkpoint inhibitor; immuno-oncology; immunotherapy; Interferon-gamma - metabolism; Lymphocyte Activation Gene 3 Protein; melanoma; Melanoma - drug therapy; Melanoma - immunology; Melanoma, Experimental - immunology; Mice; Mice, Inbred C57BL; NKG2A; Programmed Cell Death 1 Receptor - metabolism; T-Cell Exhaustion; immune checkpoint inhibitor; IFN-γ; anti-LAG-3; immunotherapy; NKG2A; melanoma; immuno-oncology; anti-tumor immunity; anti-PD-1; CD8+ T cell; CD8(+) T cell
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2024.07.016

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. [Display omitted] •PD-1- and LAG-3-deficient CD8+ T cells promote enhanced tumor clearance and survival•NKG2A impedes CD8+ T cell anti-tumor immunity following PD-1 and LAG-3 deletion•PD-1 and LAG-3 deletion increases interferon-responsive gene expression and IFN-γ release•Cell-intrinsic IFN-γ signaling promotes anti-tumor activity after PD-1 and LAG-3 deletion CD8+ T cells deficient in both PD-1 and LAG-3 exhibit altered exhaustion profiles and enhanced anti-tumor immunity driven by an autocrine IFN-γ-dependent mechanism.