Regulation of immunological tolerance by the p53-inhibitor iASPP

• Published in: Cell death & disease 2023-02, Vol.14 (2), p.84-84, Article 84
• Main Authors: Akama-Garren, Elliot H., Miller, Paul, Carroll, Thomas M., Tellier, Michael, Sutendra, Gopinath, Buti, Ludovico, Zaborowska, Justyna, Goldin, Robert D., Slee, Elizabeth, Szele, Francis G., Murphy, Shona, Lu, Xin
• Format: Article
• Language: English
• Subjects: 13/1; 13/31; 13/51; 38/39; 38/91; 631/250/1933; 631/250/38; 631/250/580; 631/67/1244; 64/60; Adenocarcinoma; Adjuvanticity; Animals; Antibodies; Antigens; Apoptosis; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmunity; Biochemistry; Biomedical and Life Sciences; Cancer; Cardiomyopathy; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell Biology; Cell Culture; Cell death; Cell Line, Tumor; Cells; Cytokines; Cytotoxicity; Disease; Homeostasis; Humans; Immune system; Immunological tolerance; Immunology; Immunoregulation; Immunosuppression; Inflammation; Influence; Inhibitor of Apoptosis Proteins - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; Lung cancer; Lymphocytes; Lymphocytes T; Mice; Myeloid cells; Neoplasms - genetics; p53 Protein; Pancreatic cancer; Phagocytosis; Proteins; Repressor Proteins - metabolism; Senescence; Tumor cells; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor-infiltrating lymphocytes; Tumorigenesis; Tumors; Wound healing
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-05567-9

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.