PD-1 endocytosis unleashes the cytolytic potential of check-point blockade in tumor immunity

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B149
Abstract ID: 6071

Presenting Author:
Andres Oroya , PD-1 endocytosis unleashes the cytolytic potential of check-point blockade in tumor immunity at Hosp. Maisonneuve-Rosemont, University de Montréal (University of Montreal)

Abstract:

PD-1 immune checkpoint blockade (ICB) has revolutionized cancer treatment. Present models indicate that anti-PD-1 operates by preventing PD-1 from binding to its ligand PD-L1. Surprisingly, ICB-mediated internalization of PD-1 and its importance have not been fully explored. Here, we demonstrate that PD-1 internalization is associated with increased cytolytic activity during cancer immunotherapy. Anti-hPD-1 and -mPD-1 antibodies induced internalization of PD-1 generating a PD-1^int subset, resistant to further internalization. Moreover, anti-PD-1 downregulation was more effective in CD8⁺ T cells than CD4⁺ T cells. ICB also induced PD-1 degradation in a proteosome-dependent manner. Interestingly, Nivolumab outperformed Pembrolizumab with both antibodies exhibiting distinct effects on CD8⁺ effector and effector memory T-cells. Importantly, PD-1 downregulation was dependent on receptor crosslinking by bivalent but not monovalent antibodies. Consistent with this, B16-PD-L1⁺ tumor-bearing mice treated with bivalent antibodies showed better anti-tumor response relative to monovalent antibodies. While mono and bivalent blockade increased granzyme B expression, only bivalent antibody induced perforin in CD8⁺ T-cells.  Our findings unveil a mechanism beyond steric blockade and underscore the significance of PD-1 endocytosis in optimizing checkpoint blockade. Targeting PD-1 internalization holds promise for enhancing anti-tumor immunity and improving the efficacy of PD-1 ICB.