iASPP as a regulator of immunological tolerance

Researchers from the Lu lab identify iASPP to be a key component in the anti-tumor immune response


How a cell dies is a key determinant of how the immune system approaches the important business of its clearance: the normal—or homeostatic—turnover of dead cells is typically met by the immune system with a tolerogenic, or immunologically silent, response; infected or malignant dead cells, meanwhile, provoke an immunogenic response that can include inflammation and the recruitment of T cells to the site. Indeed, one possible way tumors can evade the immune system is by promoting tolerogenic responses to cell death.

Although recent work has suggested that p53 mediates interactions between dying cells and the immune system, the mechanisms by which this occurs were unclear. Researchers led by Ludwig Oxford Director Xin Lu and Elliot Akama-Garren, now an alumnus of the lab, hypothesized that iASPP, a regulator of p53, may be involved in that mediation. Their study, published in Cell Death and Disease, showed that iASPP indeed participates in the maintenance of immune homeostasis.

In models of lung and pancreatic cancer, deletion of iASPP 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. The researchers also found that iASPP-deficient tumor cells and tumor-infiltrating immune cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 known to promote a tolerogenic immune response. iASPP deficiency thus seems to favor an immunosuppressive microenvironment in lung and pancreatic tumors, which in turn promotes tumor progression. Akama-Garren, Lu and colleagues suggest their findings open opportunities for the development of novel cancer immunotherapies.


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