title: PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells.
abstract: The inhibitory receptor programmed cell death 1 (PD-1) plays a major role in functional exhaustion of T cells during chronic infections and cancer, and recent clinical data suggest that blockade of the PD-1 pathway is an effective immunotherapy in treating certain cancers. Thus, it is important to define combinatorial approaches that increase the efficacy of PD-1 blockade. To address this issue, we examined the effect of IL-2 and PD-1 ligand 1 (PD-L1) blockade in the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We found that low-dose IL-2 administration alone enhanced CD8+ T cell responses in chronically infected mice. IL-2 treatment also decreased inhibitory receptor levels on virus-specific CD8+ T cells and increased expression of CD127 and CD44, resulting in a phenotype resembling that of memory T cells. Surprisingly, IL-2 therapy had only a minimal effect on reducing viral load. However, combining IL-2 treatment with blockade of the PD-1 inhibitory pathway had striking synergistic effects in enhancing virus-specific CD8+ T cell responses and decreasing viral load. Interestingly, this reduction in viral load occurred despite increased numbers of Tregs. These results suggest that combined IL-2 therapy and PD-L1 blockade merits consideration as a regimen for treating human chronic infections and cancer.
authors.affiliation: Emory Vaccine Center and Emory University School of Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: West
authors.forename: Hyun-Tak
authors.initials: HT
authors.lastname: Jin
authors.forename: Ata-Ur
authors.initials: AU
authors.lastname: Rasheed
authors.forename: Pablo
authors.initials: P
authors.lastname: Penaloza-Macmaster
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.forename: Wendy G
authors.initials: WG
authors.lastname: Tan
authors.forename: Ben
authors.initials: B
authors.lastname: Youngblood
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Kendall A
authors.initials: KA
authors.lastname: Smith
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology; D001117:Arenaviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002908:Chronic Disease; D004357:Drug Synergism; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology; D007167:Immunotherapy; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000494:pharmacology; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D019562:Viral Load / Q000187:drug effects; D014766:Viremia / Q000188:drug therapy / Q000276:immunology / Q000821:virology
chemical_list: D000906:Antibodies; D000998:Antiviral Agents; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D007155:Immunologic Factors; D007376:Interleukin-2; D053699:Interleukin-7 Receptor alpha Subunit; D061026:Programmed Cell Death 1 Receptor