Context-restricted PD-(L)1 checkpoint agonism by CTLA4-Ig therapies inhibits T cell activity
T cell surface CTLA4 sequesters the costimulatory ligands CD80 and CD86 on antigen-presenting cells (APCs) to prevent autoimmunity. Therapeutic immunosuppression by recombinant CTLA4-immunoglobulin (Ig) fusion proteins, including abatacept, is also attributed to CD80/CD86 blockade. Recent studies show that CTLA4-Ig binding to APC surface cis-CD80:PD-L1 complexes can release the inhibitory ligand PD-L1, but whether this contributes to T cell inhibition remains unclear. Here, we show that PD-L1 liberation by CTLA4-Ig is strictly limited, both in extent and context, relative to PD-L1-competing anti-CD80 antibodies. At APC surface CD80:PD-L1 ratios exceeding 2:1, CTLA4-Ig therapies fail to release PD-L1 regardless of their CD80 affinity. Additionally, introducing flexibility into CTLA4-Ig by modifying its rigid homodimer interface produces biologics that retain bivalent CD80 binding without dissociating cis-bound PD-L1. These findings demonstrate that CTLA4-Ig therapies liberate PD-L1 through a CD80 reorientation mechanism that imposes a strict context dependence to their PD-1 checkpoint agonism and resultant T cell inhibition.
Authors
- P. Mark Hogarth (ORCID: https://orcid.org/0000-0002-0360-7890)
- Meredith O’Keeffe (ORCID: https://orcid.org/0000-0002-0779-4654)
- Damian B. D’Silva
- Ross A. Dickins (ORCID: https://orcid.org/0000-0003-4112-5304)
- Lilian L. L. Wong (ORCID: https://orcid.org/0000-0001-9925-928X)
- Emily S.J. Edwards (ORCID: https://orcid.org/0000-0002-0240-4370)
- Nadia J. Kershaw (ORCID: https://orcid.org/0000-0002-3554-2622)
- Katharine J. Goodall (ORCID: https://orcid.org/0000-0001-5812-8515)
- Ee Shan Pang (ORCID: https://orcid.org/0000-0003-4325-6260)
- Josephine Iaria
- Menno C. van Zelm (ORCID: https://orcid.org/0000-0003-4161-1919)
- Nicole M. Haynes (ORCID: https://orcid.org/0000-0003-4991-6274)
- Hae-Young Park (ORCID: https://orcid.org/0000-0002-5490-0122)
- Jacinta Hansen (ORCID: https://orcid.org/0000-0001-5502-8391)
- Cynthia Louis (ORCID: https://orcid.org/0000-0001-8382-6358)
- Maximilian M. Garwood (ORCID: https://orcid.org/0009-0009-5452-7581)
- Nicholas D. Huntington (ORCID: https://orcid.org/0000-0002-5267-7211)
- Ethan P. Oxley (ORCID: https://orcid.org/0000-0002-9322-7313)
- Ian P. Wicks (ORCID: https://orcid.org/0000-0001-7050-6822)
- Veronica Tsin Fong Voo
- Ariel G. Lebenbaum
- Stephanie Wiranata
- Skye Min Jee Ho
Institutions
- The Royal Melbourne Hospital (AU)
- Burnet Institute (AU)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Peter MacCallum Cancer Centre (AU)
- Australian Regenerative Medicine Institute (AU)
- Monash University (AU)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114834
- Citations
- 5
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.41
Funders
- Bristol-Myers Squibb
- F. Hoffmann-La Roche
- John T. Reid Charitable Trusts
- Department of Health, State Government of Victoria
- National Health and Medical Research Council