Regulation of immunological tolerance by the p53-inhibitor iASPP

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 gamma delta 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.

Automated summary

Maintaining a balance between tolerance and autoimmunity is crucial for preventing human diseases. The protein p53 and its regulator iASPP play important roles in immunological tolerance and tumorigenesis. Deficiency in iASPP promotes tumor development but reduces susceptibility to autoimmune diseases. Furthermore, iASPP-deficient tumors exhibit immunosuppression characteristics, suggesting potential therapeutic opportunities for targeting the iASPP/p53 axis in autoimmune diseases and cancer.