Regulation of immunological tolerance by the p53-inhibitor iASPP.

Autor: Akama-Garren EH; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK. elliot_akama-garren@hms.harvard.edu.; Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, 02115, USA. elliot_akama-garren@hms.harvard.edu., Miller P; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK., Carroll TM; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK., Tellier M; Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK., Sutendra G; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.; Department of Medicine, University of Alberta, Edmonton, AB, T6G 2B7, Canada., Buti L; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.; Charles River Laboratories, Leiden, Netherlands., Zaborowska J; Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK., Goldin RD; Centre for Pathology, St. Mary's Hospital, Imperial College, London, W2 1NY, UK., Slee E; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK., Szele FG; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK., Murphy S; Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK., Lu X; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK. xin.lu@ludwig.ox.ac.uk.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2023 Feb 06; Vol. 14 (2), pp. 84. Date of Electronic Publication: 2023 Feb 06.
DOI: 10.1038/s41419-023-05567-9
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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