LAG3 and PD1 synergize on CD8⁺ T cells to drive T cell exhaustion and hinder autocrine IFNγ-dependent anti-tumor immunity

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Presentation Time: 02:15 PM - 02:30 PM
Abstract ID: 4179 - B

Presenting Author:
Samuel C Butler , Graduate Student Researcher at Univ. of Pittsburgh Sch. of Med.

Abstract:

Overcoming immune-mediated resistance to PD1 blockade remains a major challenge. Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD1) and relatlimab (anti-LAG3), the first in its class to be FDA-approved. However, little is known about how these two inhibitory receptors synergize to hinder anti-tumor immunity. Here, we show that PD1/LAG3-deficient CD8⁺ T cells, in contrast to CD8⁺ T cells lacking either receptor, mediate greater tumor clearance and long-term survival in mouse models of melanoma. PD1/LAG3-deficient CD8⁺ T cells are transcriptionally distinct, with broad TCR clonality, and enrichment of effector-like and interferon-responsive genes, resulting in enhanced IFNγ release indicative of functionality. LAG3 and PD1 combine to drive T cell exhaustion, playing a dominant role in modulation of TOX. Mechanistically, autocrine, cell-intrinsic IFNγ signaling is required for PD1/LAG3-deficient CD8⁺ T cells to enhance anti-tumor immunity, providing insight into how combinatorial targeting of LAG3 and PD1 results in enhanced efficacy.