| Title: |
OX40- and CD27-mmediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence |
| Authors: |
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.; Chakraverty, R. |
| Publication Year: |
2015 |
| Collection: |
University of Southampton: e-Prints Soton |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
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), 125-133. (doi:10.4049/jimmunol.1401644 ). (PMID:25404365 ) |
| Availability: |
https://eprints.soton.ac.uk/390018/ |
| Accession Number: |
edsbas.577B3CE6 |
| Database: |
BASE |