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T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition

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Science  31 Mar 2017:
Vol. 355, Issue 6332, pp. 1428-1433
DOI: 10.1126/science.aaf1292

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  • Translational implications of PD-1 biology
    • Sebastian Kobold, Consultant in Clinical Pharmacology and Immunology, Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum
    • Other Contributors:
      • Felicitas Rataj, Postdoctoral fellow, Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum
      • Johannes vom Berg, Group leader, Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland
      • Stefan Endres, Department head, Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum

    Recently, Hui et al. have reported that CD28 is the primary target of PD-1-mediated T cell inhibition, showing that active CD28 signaling is required for PD-1 to suppress T cell function [1]. We and others have recently described the use of a PD-1-CD28 fusion receptor, which – when introduced into T cells – turns PD-1 inhibition into CD28 costimulation [2-5]. In preclinical models, this approach has proven synergy both with T cell receptor- and chimeric antigen receptor-based adoptive T cell therapy [2, 4]. A major limitation of both forms of therapies is tumor-induced anergy by, among others, PD1-PD-L1 interactions. This can be reverted through appropriate engineering of the T cell or by pharmacological blockade of the PD-1-PD-L1 axis. The findings by Hui et al. have several implications for translation: first they stress the need for presence of costimulation for PD-1 blockade efficacy, in addition to primary antigen recognition. Second, this work provides an explanation for the synergy observed in our studies between PD-1 binding and combined CD28 costimulation: the work from Hui and others suggests that PD-1 functions as a monomer which interacts with CD28 molecules in a stoichiometric fashion. Apart from competing for ligand binding, a PD-1-CD28 fusion protein will not associate with another PD-1 molecule, shielding the CD28 signaling motives from SHP2-mediated dephosphorylation. This results in amplification of CD28 signaling as dephosphorylation of the endogenous CD...

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    Competing Interests: None declared.