CTLA-4: Checkpoints beyond the membrane

In 2018, the Nobel Prize in Physiology or Medicine was awarded to Professors James Allison and Tasuku Honjo for their pioneering research on CTLA-4 and PD-1. The discovery that the checkpoint receptors CTLA-4 and PD-1 regulate anti-tumor T cell immunity has revolutionized the field of cancer therapy since ipilimumab, a monoclonal antibody (mAb) specific for CTLA-4, was first shown to prolong survival in patients with difficult-to-treat metastatic melanoma over 10 years ago. While the assumption has been that CTLA-4-targeting mAbs target the membrane-bound form of CTLA-4, an understudied soluble form of CTLA-4 (sCTLA-4) has also been described. In this issue of Molecular Therapy, Kennedy et al. comprehensively demonstrate that sCTLA-4 alone confers a growth advantage to tumor cells, and importantly, a monoclonal antibody specific for sCTLA-4, and not membrane (m)CTLA-4, proved an effective therapeutic agent in vivo. 1 Kennedy P.T. Saulters E.L. Duckworth A.D. Lim Y.J. Woolley J.F. Slupsky J.R. Cragg M.S. Ward F.J. Dahal L.N. Soluble CTLA-4 attenuates T-cell activation and modulates anti-tumour immunity. Mol. Ther. 2024; 32https://doi.org/10.1016/j.ymthe.2023.11.028 Abstract Full Text Full Text PDF Scopus (0) Google Scholar The authors provide further insights into the cellular mechanisms by which sCTLA-4 and anti-sCTLA-4 alter the tumor microenvironment (TME). These findings challenge long-held assumptions about the mechanism(s) of action of anti-CTLA-4 mAbs and provide a basis for considering the clinical potential of sCTLA-4-targeting mAbs. Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunityKennedy et al.Molecular TherapyDecember 4, 2023In BriefThe role of soluble CTLA-4 in the immune regulation of cancer is poorly understood. In this study, Kennedy et al. identify a novel checkpoint function of this isoform, revealing it to suppress anti-tumor immunity and leverage therapy through its blockade. Full-Text PDF Open Access