AB0034 PD-1 AGONISM INHIBITS ACTIVATION OF PLASMACYTOID DENDRITIC CELLS
Authors: I. Banerjee, L. Edwards, P. Halvey, S. Alioto, D. Cluckley, C. Mitchell, C. Cox, E. Lurier, M. Cianci, S. Bengeri, S. Borthakur, K. Kis-Toth, N. Higginson-Scott, J. Viney, K. L. Otipoby
Journal: Annals of the Rheumatic Diseases (2021)

Background: T cell function is regulated by complex signaling networks of interconnected activators and inhibitors. Blockade of inhibitory receptors such as programmed death-1 (PD-1) has emerged as a novel treatment for multiple forms of cancer. One of the most common adverse events associated with blockade of the endogenous PD-1/PD-L1 pathway is the induction of autoimmune pathology in multiple tissues, demonstrating that PD-1 activation is necessary for normal immune homeostasis in humans (Kostine, et al., 2018). Given this body of clinical data, we sought to develop a PD-1 agonist antibody as a therapeutic approach to restore immune homeostasis in patients living with autoimmune diseases. PD-1 expression and function has been primarily described on T cells (Ishida, et al., 1992), with additional data available from several other immune cell populations (Ohaegbulam, et al., 2015). Objectives: To study the effect of PD-1 agonism on plasmacytoid dendritic cell (pDC) function. Methods: Human PBMCs stimulated with or without toll-like receptor (TLR)-9 agonist, CpG were analyzed by flow cytometry for PD-1 expression on immune cell subsets. To assess the impact of PD-1 agonist on pDC function human PBMCs were activated by CpG in the presence or absence of PD-1 agonist. Type-I interferon (IFN) levels were quantified using ELISA from culture supernatants. The expression of interferon stimulated genes was analyzed by qPCR as a measure of type-I IFN activation. Results: We have discovered that TLR9 activation can induce PD-1 expression on plasmacytoid dendritic cells, which has not been previously reported. Further, we have demonstrated that PD-1 agonism inhibits TLR9-mediated activation and the effector functions of plasmacytoid dendritic cells. Conclusion: These data suggest the potential of PD-1 as a target for regulating diseases with pathology generated by type-I IFN. References: [1]Ishida, Y., Agata, Y., Shihibahara, K., &amp; Honjo, T. (1992). Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. , 11(11):3887-95. [2]Kostine, M., Rouxel, L., Barnetche, T., Veillon, R., Martin, F., Dutriaux, C., . . . Schaeverbeke, T. (2018). Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Annual Rheumatic Disease , 77(3):393-398. [3]Ohaegbulam, K. C., Assal, A., Lazar-Molnar, E., Yao, Y., &amp; Zang, X. (2015). Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends in Molecular Medicine , 21(1); 24-33. Disclosure of Interests: Ishita Banerjee Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Lindsay Edwards Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Patrick Halvey Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Salvatore Alioto Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, David Cluckley Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Caitlin Mitchell Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Christopher Cox Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Emily Lurier Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Michael Cianci Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Soumya Bengeri Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Susmita Borthakur Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Katalin Kis-Toth Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Nathan Higginson-Scott Shareholder of: Pandion Therapeutics, Consultant of: Biotech Companies, Employee of: Pandion Therapeutics, Jo Viney Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Kevin L. Otipoby Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics