Context-restricted PD-(L)1 checkpoint agonism by CTLA4-Ig therapies inhibits T cell activity
Year: 2024
Type: article
Abstract: 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.
Source: Cell Reports
Authors: 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
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,460
OpenAlex ID: W4403228155