Context-restricted PD-(L)1 checkpoint agonism by CTLA4-Ig therapies inhibits T cell activity
Ethan P. Oxley,
Nadia J. Kershaw,
Cynthia Louis,
Katharine J. Goodall,
Maximilian M. Garwood,
Skye Min Jee Ho,
Veronica T.F. Voo,
Hae-Young Park,
Josephine Iaria,
Lilian L.L. Wong,
Ariel G. Lebenbaum,
Stephanie Wiranata,
Ee Shan Pang,
Emily S.J. Edwards,
Damian B. D’Silva,
Jacinta Hansen,
Menno C. van Zelm,
Meredith O’Keeffe,
P. Mark Hogarth,
Nicole M. Haynes,
Nicholas D. Huntington,
Ian P. Wicks,
Ross A. Dickins
Affiliations
Ethan P. Oxley
Australian Centre for Blood Diseases, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia
Nadia J. Kershaw
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Royal Parade, Parkville, VIC 3052, Australia
Cynthia Louis
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Royal Parade, Parkville, VIC 3052, Australia
Katharine J. Goodall
Australian Centre for Blood Diseases, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia
Maximilian M. Garwood
Australian Centre for Blood Diseases, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia
Skye Min Jee Ho
Australian Centre for Blood Diseases, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia
Veronica T.F. Voo
Australian Centre for Blood Diseases, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia
Hae-Young Park
Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Josephine Iaria
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia
Lilian L.L. Wong
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia
Ariel G. Lebenbaum
Australian Centre for Blood Diseases, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia
Stephanie Wiranata
Australian Centre for Blood Diseases, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia
Ee Shan Pang
Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Emily S.J. Edwards
Department of Immunology and Pathology, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia
Damian B. D’Silva
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia
Jacinta Hansen
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia
Menno C. van Zelm
Department of Immunology and Pathology, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia; Department of Allergy, Immunology & Respiratory Medicine, Monash University, Melbourne, VIC 3004, Australia
Meredith O’Keeffe
Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
P. Mark Hogarth
Burnet Institute, 85 Commercial Road, Melbourne, VIC 3004, Australia; Department of Clinical Pathology, The University of Melbourne, Royal Parade, Parkville, VIC 3052, Australia
Nicole M. Haynes
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville VIC 3052, Australia
Nicholas D. Huntington
Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Ian P. Wicks
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Royal Parade, Parkville, VIC 3052, Australia
Ross A. Dickins
Australian Centre for Blood Diseases, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia; Corresponding author
Summary: 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.
