title: Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation.
abstract: Tumors have evolved multiple mechanisms to evade immune destruction. One of these is expression of T cell inhibitory ligands such as programmed death-ligand 1 (PD-L1; B7-H1). In this study, we show that PD-L1 is highly expressed on mesothelioma tumor cells and within the tumor stroma. However, PD-L1 blockade only marginally affected tumor growth and was associated with the emergence of activated programmed death-1(+) ICOS(+) CD4 T cells in tumor-draining lymph nodes, whereas few activated CD8 T cells were present. Full activation of antitumor CD8 T cells, characterized as programmed death-1(+) ICOS(+) Ki-67(+) and displaying CTL activity, was only observed when CD4 T cells were depleted, suggesting that a population of suppressive CD4 T cells exists. ICOS(+) foxp3(+) regulatory T cells were found to be regulated through PD-L1, identifying one potentially suppressive CD4 T cell population. Thus, PD-L1 blockade activates antitumor CD8 T cell most potently in the absence of CD4 T cells. These findings have implications for the development of PD-L1-based therapies.
authors.affiliation: National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Currie
authors.forename: Amy
authors.initials: A
authors.lastname: Prosser
authors.forename: Alison
authors.initials: A
authors.lastname: McDonnell
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Cleaver
authors.forename: Bruce W S
authors.initials: BW
authors.lastname: Robinson
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Robbert G
authors.initials: RG
authors.lastname: van der Most
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D000075202:Contraindications; D005260:Female; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008654:Mesothelioma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010455:Peptides / Q000037:antagonists & inhibitors / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor