Immune Inhibitory Molecules LAG-3 and PD-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape

作者：Seng‐Ryong Woo, Meghan E. Turnis, Monica V. Goldberg, Jaishree Bankoti, Mark Selby, Christopher J. Nirschl, Matthew L. Bettini, David M. Gravano, Peter Vogel, Chih Long Liu, Stephanie Tangsombatvisit, Joseph F. Grosso, George J. Netto, Matthew P. Smeltzer, Alcides Chaux, Paul J. Utz, Creg J. Workman, Drew M. Pardoll, Alan J. Korman, Charles G. Drake, Dario A.A. Vignali · 发表于：Cancer Research · 年份：2011 · DOI：10.1158/0008-5472.can-11-1620 · 被引用次数：1662 · 研究领域：Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research、Neuroblastoma Research and Treatments

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.