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Cell-targeted PD-1 agonists are potent NK-cell inhibitors.

Harriet C Pope1,2, Ana L Chiodetti1, Alice Newey1

  • 1Immunocore Ltd., Abingdon, United Kingdom.

Frontiers in Immunology
|September 8, 2025
PubMed
Summary

A novel bispecific molecule targeting PD-1 (programmed cell death protein 1) agonists to pancreatic beta cells suppresses NK cell activity, offering potential treatments for autoimmune diseases.

Keywords:
NK cellNK cell inhibitionPD-1 pathwayautoimmune diseasescell-targeted PD-1 agoniststype 1 diabetes

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Area of Science:

  • Immunology
  • Cell Biology
  • Therapeutics

Background:

  • Programmed cell death protein 1 (PD-1) is a critical immune checkpoint targeted in cancer and inflammatory diseases.
  • NK cells express PD-1 upon activation and their functions are modulated by this pathway.
  • PD-1 agonists can induce immune suppression, beneficial for inflammatory conditions.

Purpose of the Study:

  • To develop and assess a novel bispecific molecule that targets PD-1 agonists to pancreatic beta cells.
  • To evaluate the molecule's ability to suppress NK cell activity in a targeted manner.

Main Methods:

  • A bispecific molecule was engineered with a beta-cell targeting domain and a PD-1 agonist effector domain.
  • NK cell and NK92-PD-1 cell line activation was assessed via gene expression, degranulation marker (CD107a), IFNγ, and Granzyme B secretion.
  • Pancreatic beta-cell proliferation and insulin production were also measured.

Main Results:

  • The beta-cell tethered bispecific PD-1 agonist molecule localized to the immunological synapse.
  • This molecule altered NK cell gene expression, reducing inflammatory and cytotoxic functions.
  • No significant impact on beta-cell proliferation or insulin production was observed.

Conclusions:

  • Targeted PD-1 agonist molecules can inhibit T cells and NK cells in a tissue-specific manner.
  • This approach presents a promising therapeutic strategy for autoimmune and inflammatory diseases.
  • The developed molecule demonstrates potential for localized immune suppression in autoimmune conditions affecting pancreatic beta cells.