GPANK1-PTEN信号轴调控髓源性抑制细胞精细分化促进三阴乳腺癌发生: 基于胚系基因组的机制研究

持久免疫抑制是促进三阴乳腺癌发病的关键因素之一。我们前期在胚系基因组全局性功能层面证明了罕见遗传变异的联合效应驱动免疫抑制的发生，且抑制程度与发病风险高度相关；在细胞功能层面，较之健康对照，三阴乳腺癌患者外周血髓源性抑制细胞(MDSC)出现精细分化和增殖，但分子调控机制不明。分析显示GPANK1可能调控MDSC分化增殖而抑制免疫促进肿瘤发生。本项目拟：①结合遗传学、基因组学、知识与数据混合驱动的深度学习方法建立模型评估人群免疫功能和三阴乳腺癌患病风险;②以免疫单细胞技术鉴定MDSC的精细亚型作为三阴乳腺癌更准确的免疫功能评估指标;③检测MDSC中GPANK1的变化，建立模型验证GPANK1通过抑制PTEN调控MDSC分化与增殖、抑制免疫并最终促进肿瘤形成的机制。本项目从胚系基因组变异入手，深究三阴乳腺癌免疫抑制的可能机制并探索潜在治疗靶点，为三阴乳腺癌免疫干预、解除免疫抑制提供全新策略

Persistent immune suppression is one of the key factors that promotes triple negative breast cancer (TNBC) pathogenesis. Previously, at the global functional level of the germline genome, we have demonstrated that the combined effect of rare genetic variations encodes immunosuppression in TNBC patients, and revealed the quantitative relationship between the degree of immunosuppression determined by the rare genetic variants and the risk of TNBC disease. Furthermore, at the level of cellular function, we have discovered that myeloid-derived suppressor cells (MDSC) in the peripheral blood of TNBC patients undergoes fine differentiation and proliferation when compared with healthy controls, but the molecular regulatory mechanism is still unknown. Our preliminary analysis demonstrated that GPANK1 might regulate the differentiation and proliferation of MDSCs, and then suppress immunity to promote tumorigenesis. Therefore, our project intends to: ① establish a model that combines genetics, genomics, knowledge, and data-driven deep learning methods to assess the population's immune function and the risk of triple negative breast cancer; ② use immune-single cell technology to identify the subtypes of MDSC and verify it to create a more accurate evaluation index for immune function in triple-negative breast cancer; ③ detect the changes of GPANK1 in MDSC, and establish an animal model to deeply study the mechanism by which GPANK1 interacts with PTEN to regulates the fine differentiation and proliferation of MDSC, suppresses immunity, and ultimately promotes cancer formation. We begin with germline genome mutations to deeply explore the possible immunosuppression mechanisms in TNBC patients, and we expected to provide new strategies for relieving immunosuppression and likely help TNBC patients avoid this deadly disease.