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Regulation of immunological tolerance by the p53-inhibitor iASPP

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posted on 2023-06-30, 08:39 authored by Elliot H Akama-Garren, Paul Miller, Thomas M Carroll, Michael Tellier, Gopinath Sutendra, Ludovico Buti, Justyna Zaborowska, Robert D Goldin, Elizabeth Slee, Francis G Szele, Shona Murphy, Xin Lu

Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and γδ T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.

Funding

Ludwig Institute for Cancer Research and Rhodes Scholarships

Medical Scientist Training Program

National Institute of General Medical Sciences

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Training in Transplantation Biology

National Institute of Allergy and Infectious Diseases

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Follicular helper T cells as drivers of epitope spreading

National Institute of Allergy and Infectious Diseases

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grants WT106134AIA and WT210641/Z/18/Z from the Wellcome Trust

History

Author affiliation

Department of Molecular and Cell Biology, University of Leicester

Version

  • VoR (Version of Record)

Published in

Cell Death & Disease

Volume

14

Issue

2

Publisher

Springer Science and Business Media LLC

eissn

2041-4889

Copyright date

2023

Available date

2023-06-30

Language

en

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