title: OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence.
abstract: Exhaustion of chronically stimulated CD8(+) T cells is a significant obstacle to immune control of chronic infections or tumors. Although coinhibitory checkpoint blockade with anti-programmed death ligand 1 (PD-L1) Ab can restore functions to exhausted T cell populations, recovery is often incomplete and dependent upon the pool size of a quiescent T-bet(high) subset that expresses lower levels of PD-1. In a model in which unhelped, HY-specific CD8(+) T cells gradually lose function following transfer to male bone marrow transplantation recipients, we have explored the effect of shifting the balance away from coinhibition and toward costimulation by combining anti-PD-L1 with agonistic Abs to the TNFR superfamily members, OX40 and CD27. Several weeks following T cell transfer, both agonistic Abs, but especially anti-CD27, demonstrated synergy with anti-PD-L1 by enhancing CD8(+) T cell proliferation and effector cytokine generation. Anti-CD27 and anti-PD-L1 synergized by downregulating the expression of multiple quiescence-related genes concomitant with a reduced frequency of T-bet(high) cells within the exhausted population. However, in the presence of persistent Ag, the CD8(+) T cell response was not sustained and the overall size of the effector cytokine-producing pool eventually contracted to levels below that of controls. Thus, CD27-mediated costimulation can synergize with coinhibitory checkpoint blockade to switch off molecular programs for quiescence in exhausted T cell populations, but at the expense of losing precursor cells required to maintain a response.
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton.
authors.forename: Sarah
authors.initials: S
authors.lastname: Buchan
authors.affiliation: Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.
authors.forename: Teresa
authors.initials: T
authors.lastname: Manzo
authors.affiliation: Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.
authors.forename: Barry
authors.initials: B
authors.lastname: Flutter
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton.
authors.forename: Anne
authors.initials: A
authors.lastname: Rogel
authors.affiliation: Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.
authors.forename: Noha
authors.initials: N
authors.lastname: Edwards
authors.affiliation: Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.
authors.forename: Shivajanani
authors.initials: S
authors.lastname: Sivakumaran
authors.affiliation: Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.
authors.forename: Sara
authors.initials: S
authors.lastname: Ghorashian
authors.affiliation: Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.
authors.forename: Ben
authors.initials: B
authors.lastname: Carpenter
authors.affiliation: Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.
authors.forename: Clare
authors.initials: C
authors.lastname: Bennett
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York.
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
authors.affiliation: Institute of Allergy and Immunology, La Jolla.
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton.
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
authors.affiliation: Transplantation Immunology Group, Cancer Institute and Institute for Immunity and Transplantation, University College London.
authors.forename: Ronjon
authors.initials: R
authors.lastname: Chakraverty
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000276:immunology*; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D005260:Female; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053278:OX40 Ligand; D053262:Receptors, OX40 / Q000235:genetics / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D000906:Antibodies; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors