Recent research has suggested that the tumor suppressor p53 mediates interactions between dying cells and the immune system, but the mechanisms by which this occurs were unclear. Researchers co-led by Ludwig Oxford Director Xin Lu suspected that iASPP, a regulator of p53, may be involved in that mediation and demonstrated in a February publication in Cell Death & Disease that the protein indeed regulates immune tolerance in response to cell death. This is of relevance to cancer progression because one way tumors can evade immune clearance is by promoting immunologically silent—or tolerogenic—responses to the detritus of their constituent cancer cells, which should normally elicit inflammatory immune responses. Xin and her colleagues showed that in models of lung and pancreatic cancer, deletion of the iASPP gene promoted tumorigenesis and the immune response to these tumors exhibited hallmarks of immunosuppression, such as the presence of activated regulatory T cells and exhausted CD8+ T cells. They found that iASPP-deficient tumor cells and tumor-infiltrating immune cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes a tolerogenic immune response. iASPP deficiency thus seems to favor an immunosuppressive microenvironment in lung and pancreatic tumors, which in turn promotes tumor progression. The findings should open opportunities for the development of novel therapies against cancer and autoimmune disease.
Regulation of immunological tolerance by the p53-inhibitor iASPP
Cell Death & Disease, 2023 February 6