title: Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia.
abstract: Tumor-induced immune defects can weaken host immune response and permit tumor cell growth. In a systemic model of murine acute myeloid leukemia (AML), tumor progression resulted in increased regulatory T cells (Treg) and elevation of program death-1 (PD-1) expression on CD8(+) cytotoxic T cells (CTLs) at the tumor site. PD-1 knockout mice were more resistant to AML despite the presence of similar percentage of Tregs compared with wild type. In vitro, intact Treg suppression of CD8(+) T-cell responses was dependent on PD-1 expression by T cells and Tregs and PD-L1 expression by antigen-presenting cells. In vivo, the function of adoptively transferred AML-reactive CTLs was reduced by AML-associated Tregs. Anti-PD-L1 monoclonal antibody treatment increased the proliferation and function of CTLs at tumor sites, reduced AML tumor burden, and resulted in long-term survivors. Treg depletion followed by PD-1/PD-L1 blockade showed superior efficacy for eradication of established AML. These data demonstrated that interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression of T-effector cells and dampen the antitumor immune response. PD-1/PD-L1 blockade coupled with Treg depletion represents an important new approach that can be readily translated into the clinic to improve the therapeutic efficacy of adoptive AML-reactive CTLs in advanced AML disease.
authors.affiliation: Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Munger
authors.forename: Steven L
authors.initials: SL
authors.lastname: Highfill
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: Megan
authors.initials: M
authors.lastname: Riddle
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Vallera
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D060890:B7-H1 Antigen; D016827:CD8 Antigens / Q000276:immunology; D015973:Gene Expression Regulation, Leukemic; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D008212:Lymphocyte Depletion; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D016827:CD8 Antigens; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor