An important function of the immune system is the effective clearance of dead cells. The exact nature of a cell’s death is a key determinant of how the immune system approaches this task: in physiological conditions, the normal, homeostatic turnover of dead cells is typically met by the immune system with a tolerogenic or “immunologically silent” response, whilst infected or malignant dead cells provoke an immunogenic response, which may include inflammation and T-cell recruitment. One possible way tumours can evade the immune system is to promote tolerogenic responses to cell death.
Although recent work has suggested p53 to be a mediator between dying cells and the immune system, the mechanisms by which this occurs have remained largely unknown. Elliot Akama-Garren from the Lu lab at Ludwig Oxford, along with collaborators, hypothesized that iASPP, a regulator of p53, may be involved. Their results, published in Cell Death and Disease, show that iASPP does indeed have a role in the maintenance of immune homeostasis.
In models of lung and pancreatic cancer, deletion of iASPP promoted tumorigenesis, and the immune response to these tumours exhibited hallmarks of immunosuppression, such as the presence of activated regulatory T cells and exhausted CD8+ T cells. They also determined that iASPP-deficient tumour cells contained elevated levels of PD-1H, a transcriptional target of p53 which has been shown to promote a tolerogenic immune response. iASPP deficiency therefore favours an immunosuppresive microenvironment in the case of lung and pancreatic tumours, which contributes to the acceleration of tumour progression.
This work underlines the importance of the iASPP/p53 complex in determining the equilibrium between immunogenic and tolerogenic cell death, and its critical role in establishing an anti-tumour immune response.