OX40- and CD27-Mediated costimulation synergizes with Anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence
Authors: Buchan, S.L. et al.
Journal: Journal of Immunology
Volume: 194
Issue: 1
Pages: 125-133
eISSN: 1550-6606
ISSN: 0022-1767
DOI: 10.4049/jimmunol.1401644
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-bethigh 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-bethigh 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.
Source: Scopus
OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence.
Authors: Buchan, S. et al.
Journal: J Immunol
Volume: 194
Issue: 1
Pages: 125-133
eISSN: 1550-6606
DOI: 10.4049/jimmunol.1401644
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.
Source: PubMed
OX40-and CD27-Mediated Costimulation Synergizes with Anti-PD-L1 Blockade by Forcing Exhausted CD8<SUP>+</SUP> T Cells To Exit Quiescence
Authors: Buchan, S.L. et al.
Journal: JOURNAL OF IMMUNOLOGY
Volume: 194
Issue: 1
Pages: 125-133
eISSN: 1550-6606
ISSN: 0022-1767
DOI: 10.4049/jimmunol.1401644
Source: Web of Science (Lite)
OX40- and CD27-mediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence.
Authors: Buchan, S. et al.
Journal: Journal of immunology (Baltimore, Md. : 1950)
Volume: 194
Issue: 1
Pages: 125-133
eISSN: 1550-6606
ISSN: 0022-1767
DOI: 10.4049/jimmunol.1401644
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.
Source: Europe PubMed Central