Abstract 6528: Anti-PD-1 induces the endocytosis of the co-receptor from the surface of T-cells: Nivolumab is more effective than Pembrolizumab

Abstract Immune checkpoint blockade (ICB) has revolutionized the treatment of cancer. Present models show that anti-PD-1 operates simply by blocking co-receptor binding to its ligand PD-L1. Surprisingly, no previous studies have assessed whether ICB also induces the internalization or endocytosis of PD-1 from the cell surface. Many, but not all receptors, undergo endocytosis upon antibody or ligand binding. In this study, PD-1 internalization was assessed on activated human T cells by flow cytometry and fluorescence microscopy. Immunoprecipitation and western blotting were performed to assess the destiny of PD-1 after internalization. Our results report that anti-PD-1 induces the rapid internalization of PD-1 from the surface of T-cells in a manner comparable to CD28. A substantial minority of receptors were also resistant to antibody-induced endocytosis. Further, Nivolumab was considerably more effective than Pembrolizumab in inducing the endocytosis of PD-1 in primary human T-cells. This difference was the result of several factors where Nivolumab bound to a greater number of PD-1 molecules on the surface of T-cells than Pembrolizumab, indicating that the co-receptor might exist with different conformations on activated cells. Moreover, Nivolumab induced more rapid endocytosis (5.5 versus 3.6% per minute) and a greater percentage of PD-1 molecules than Pembrolizumab (70% versus 50%). The relative effect of anti-PD-1 molecules on internalization was seen equally on activated CD4 helper and CD8+ effector/memory T-cells. The internalization and the degradation of PD-1 were partially blocked by the inhibition of clathrin-mediated endocytosis and proteasome activity. Our studies show for the first time that ICB involves a second level of modulation involving the internalization of PD-1 from the surface of T-cells, an event which will contribute to the efficacy of ICB. Citation Format: Elham Ben Saad, Andres Oroya, Christopher E. Rudd. Anti-PD-1 induces the endocytosis of the co-receptor from the surface of T-cells: Nivolumab is more effective than Pembrolizumab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6528.

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