Context-restricted PD-(L)1 checkpoint agonism by CTLA4-Ig therapies inhibits T cell activity

Oxley, EP; Kershaw, NJ; Louis, C; Goodall, KJ; Garwood, MM; Jee Ho, SM; Voo, VTF; Park, HY; Iaria, J; Wong, LLL; Lebenbaum, AG; Wiranata, S; Pang, ES; Edwards, ESJ; D&#39;Silva, DB; Hansen, J; van Zelm, MC; O&#39;Keeffe, M; Hogarth, PM; Haynes, NM; Huntington, ND; Wicks, IP; Dickins, RA

Author(s): Oxley, EP; Kershaw, NJ; Louis, C; Goodall, KJ; Garwood, MM; Jee Ho, SM; Voo, VTF; Park, HY; Iaria, J; Wong, LLL; Lebenbaum, AG; Wiranata, S; Pang, ES; Edwards, ESJ; D'Silva, DB; Hansen, J; van Zelm, MC; O'Keeffe, M; Hogarth, PM; Haynes, NM; Huntington, ND; Wicks, IP; Dickins, RA;
Details: Publication Year 2024-10-08,Volume 43,Issue #10,Page 114834
Journal Title: Cell Reports
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.
Publisher: Cell Press
Research Division(s): Structural Biology; Blood Cells And Blood Cancer; Inflammation
PubMed ID: 39383033
Publisher's Version: https://doi.org/10.1016/j.celrep.2024.114834
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2024.114834
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: PIIS2211124724011859.pdf - (5.23MB, application/pdf)

Creation Date: 2024-10-25 10:15:36

Last Modified: 2024-10-25 10:42:50