OX40- and CD27-mmediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence
OX40- and CD27-mmediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence
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.
125-133
Buchan, S.
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Manzo, T.
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Flutter, B.
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Rogel, A.
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Edwards, N.
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Zhang, L.
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Sivakumaran, S.
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Ghorashian, S.
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Carpenter, B.
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Bennett, C.L.
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Freeman, G.J.
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Sykes, M.
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Croft, M.
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Al-Shamkhani, A.
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Chakraverty, R.
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1 January 2015
Buchan, S.
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Manzo, T.
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Flutter, B.
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Rogel, A.
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Edwards, N.
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Zhang, L.
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Sivakumaran, S.
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Ghorashian, S.
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Carpenter, B.
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Bennett, C.L.
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Freeman, G.J.
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Sykes, M.
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Croft, M.
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Al-Shamkhani, A.
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Chakraverty, R.
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Buchan, S., Manzo, T., Flutter, B., Rogel, A., Edwards, N., Zhang, L., Sivakumaran, S., Ghorashian, S., Carpenter, B., Bennett, C.L., Freeman, G.J., Sykes, M., Croft, M., Al-Shamkhani, A. and Chakraverty, R.
(2015)
OX40- and CD27-mmediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence.
Journal of Immunology, 194 (1), .
(doi:10.4049/jimmunol.1401644).
(PMID:25404365)
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.
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Accepted/In Press date: 22 October 2014
e-pub ahead of print date: 17 November 2014
Published date: 1 January 2015
Organisations:
Faculty of Medicine
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Local EPrints ID: 390018
URI: http://eprints.soton.ac.uk/id/eprint/390018
ISSN: 0022-1767
PURE UUID: d1acf64d-64e1-4eb7-9769-61f9b3722b54
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Date deposited: 17 Mar 2016 11:59
Last modified: 15 Mar 2024 03:00
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Author:
S. Buchan
Author:
T. Manzo
Author:
B. Flutter
Author:
A. Rogel
Author:
N. Edwards
Author:
L. Zhang
Author:
S. Sivakumaran
Author:
S. Ghorashian
Author:
B. Carpenter
Author:
C.L. Bennett
Author:
G.J. Freeman
Author:
M. Sykes
Author:
M. Croft
Author:
R. Chakraverty
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