title: Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape.
abstract: 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.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Seng-Ryong
authors.initials: SR
authors.lastname: Woo
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Turnis
authors.forename: Monica V
authors.initials: MV
authors.lastname: Goldberg
authors.forename: Jaishree
authors.initials: J
authors.lastname: Bankoti
authors.forename: Mark
authors.initials: M
authors.lastname: Selby
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nirschl
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Bettini
authors.forename: David M
authors.initials: DM
authors.lastname: Gravano
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Chih Long
authors.initials: CL
authors.lastname: Liu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tangsombatvisit
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grosso
authors.forename: George
authors.initials: G
authors.lastname: Netto
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Smeltzer
authors.forename: Alcides
authors.initials: A
authors.lastname: Chaux
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.forename: Creg J
authors.initials: CJ
authors.lastname: Workman
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.forename: Charles G
authors.initials: CG
authors.lastname: Drake
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D007108:Immune Tolerance / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000502:physiology*; D019139:Tumor Escape / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000906:Antibodies; D015703:Antigens, CD; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse