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Immune Inhibitory Molecules LAG-3 And PD-1 Synergistically Regulate T-cell Function To Promote Tumoral Immune Escape.

Seng-Ryong Woo, Meghan E. Turnis, Monica V. Goldberg, Jaishree Bankoti, M. Selby, Christopher J Nirschl, Matthew L Bettini, D. Gravano, P. Vogel, C. Liu, Stephanie Tangsombatvisit, Joseph F. Grosso, G. Netto, M. Smeltzer, Alcides Chaux, P. Utz, C. Workman, D. Pardoll, A. Korman, C. Drake, D. Vignali
Published 2012 · Biology, Medicine

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Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4(+) and CD8(+) T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3(-/-)Pdcd1(-/-) mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.
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