| Title: |
OX40- and CD27-Mediated Costimulation Synergizes with Anti–PD-L1 Blockade by Forcing Exhausted CD8+ T Cells To Exit Quiescence |
| Authors: |
Buchan, Sarah L; Manzo, Teresa; Flutter, Barry; Rogel, Anne; Edwards, Noha; Zhang, Lei; Sivakumaran, Shivajanani; Ghorashian, Sara; Carpenter, Ben; Bennett, Clare L; Freeman, Gordon J; Sykes, Megan; Croft, Michael; Al-Shamkhani, Aymen; Chakraverty, Ronjon |
| Source: |
The Journal of Immunology ; volume 194, issue 1, page 125-133 ; ISSN 0022-1767 1550-6606 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2014 |
| 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-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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.4049/jimmunol.1401644 |
| Availability: |
https://doi.org/10.4049/jimmunol.1401644; https://academic.oup.com/jimmunol/article-pdf/194/1/125/62236144/1401644.pdf |
| Rights: |
https://academic.oup.com/pages/standard-publication-reuse-rights |
| Accession Number: |
edsbas.D48A5A |
| Database: |
BASE |