iASPP in the balance between tolerance and autoimmunity

Thesis

Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Adaptive immune responses require both antigenicity and adjuvanticity, and cell death can critically influence immunological homeostasis by modulating the adjuvanticity it elicits. Accumulating evidence suggests that in addition to inducing apoptosis, p53 mitigates phagocytosis-induced adjuvanticity thereby promoting tolerance following physiologic tissue turnover. Here I identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity widely considered to be oncogenic, as a novel master regulator of immunological tolerance. Surprisingly, iASPP deficiency promoted oncogenic K-ras driven lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP deficient mice were less susceptible to autoimmune disease. Furthermore, immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8⁺ T cells, and iASPP-deficient CD4⁺ T cells were less responsive to TCR engagement in vitro. Interestingly, iASPP-deficient tumor cells, myeloid cells, CD4+, and γδ T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. These findings suggest that iASPP can inhibit p53-mediated immunosuppressive PD-1H cross-talk between malignant cells, phagocytes, and responding immune cells, thereby promoting adjuvanticity following phagocytosis. Identification of a novel iASPP/p53 axis of immune homeostasis provides an exciting therapeutic opportunity for both autoimmune disease and cancer.

Authors: Akama-Garren, E

• DOI: 10.5287/ora-j2agxkr2w
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Keywords: iASPP; Apoptosis; P53
• Subjects: Autoimmunity; Cancer; Immunology