Regulation of Immunological Tolerance by the p53-Inhibitor iASPP [mNET-Seq]

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. Overall design: mNET-seq of total RNA polymerase II in A549 wild-type cells or A549 PPP1R13L knockdown cells.维持免疫耐受与自身免疫之间的免疫稳态（immunological homeostasis），对于预防从自身免疫病到癌症的各类人类疾病至关重要。越来越多的研究证据表明，p53可抑制吞噬作用诱导的佐剂活性，从而在程序性细胞死亡后促进免疫耐受。本研究鉴定出凋亡刺激p53蛋白抑制剂（Inhibitor of Apoptosis Stimulating p53 Protein, iASPP）——一种p53转录活性的负调控因子——作为免疫耐受的调控因子。iASPP缺陷会促进肺腺癌与胰腺癌的发生，而iASPP缺陷型小鼠对自身免疫病的易感性显著降低。针对iASPP缺陷型肿瘤的免疫应答呈现免疫抑制的典型特征，包括活化的调节性T细胞与耗竭型CD8+ T细胞。值得注意的是，iASPP缺陷型肿瘤细胞、肿瘤浸润髓系细胞、CD4+ T细胞及γδ T细胞均高表达PD-1H——一种新近被鉴定的p53转录靶点，可促进耐受性吞噬作用。鉴定出调控免疫稳态的iASPP/p53信号轴，可为自身免疫病与癌症提供全新的治疗策略。实验设计：对野生型A549细胞或PPP1R13L敲低的A549细胞中的总RNA聚合酶II进行mNET-seq测序。