RAGE调控胰腺癌形成的免疫逃逸分子机制

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer. New therapies are urgently needed to impact PDAC treatment and to extend and save PDAC patients’ lives. The hypoxic and immunosuppressive tumor microenvironment (TME) is an important aspect of PDAC biology that contributes to tumor initiation, progression, and responses to therapy. One of the most promising approaches that we are currently investigating is targeting the receptor for advanced glycation endproducts (RAGE) in the PDAC TME. We hypothesize that RAGE expression in multiple components of the TME is critical for tumor evasion from T cell surveillance in PDAC. We will exploit molecular, cellular, and transgenetic animal models to pursue the following aims. Aim 1. Identify the transcriptional regulation mechanism of RAGE-mediated immune checkpoints expression. Aim 2. Identify the metabolic regulation mechanism of RAGE-mediated immune checkpoints expression. Aim 3. Define the cell-specific role of RAGE in oncogenic K-Ras-driven PDAC in mice. Aim 3. Investigate antitumor efficacy of the combination of the RAGE inhibitor with chemoimmunotherapy in different tumor models in mice. Collectively, this project builds upon our prior work to provide a more in-depth understanding of oncogenic RAGE signaling in PDAC. The hypothesis is novel and the results may lead to novel therapeutics for the treatment of pancreatic cancer.

胰腺癌是一种恶性程度极高的消化系统肿瘤。肿瘤微环境形成的免疫逃逸机制是胰腺癌发生发展的关键，也是免疫治疗的热点和难点。申请人的系列研究表明晚期糖基化终末产物受体（RAGE）是一种新型的胰腺癌致病基因，参与肿瘤生长以及多药耐药的形成。在此研究基础之上，申请者提出“RAGE是介导胰腺癌免疫逃逸的关键分子”的科学假说。针对上述假说，本项目拟选用基因工程动物、胰腺癌细胞和T细胞为主要研究材料，采用CRISPR/Cas9基因编辑等研究手段，在整体、细胞和分子水平，进一步深入系统的探讨RAGE调控胰腺癌肿瘤微环境免疫检查点表达的转录和代谢分子机制，探索基因或药物干预RAGE通路防止胰腺癌的手段。开展本项目可望揭示RAGE在胰腺癌肿瘤微环境的关键作用，为肿瘤免疫的研究开辟新的领域，为寻找胰腺癌治疗药物和检测手段提供新的思路与实验线索，具有重要的科学意义和潜在的应用前景。

胰腺癌是一种进展快、预后差、对人类健康影响极大的消化系统恶性肿瘤。肿瘤微环境在胰腺癌发生、发展中起到了至关重要的作用。晚期糖基化终末产物受体（RAGE）是一种重要的免疫调控蛋白，成为人类疾病治疗的新靶点。在国自然科学基金等资助下，项目组近年来系列研究表明是RAGE一种新型的胰腺癌致病基因，参与肿瘤生长以及多药耐药的形成。项目组在本项基金的资助下获得了一系列重要创新性成果：发现RAGE-ALOX5通路通过调节caspase-11炎性小体的激活抑制巨噬细胞发生焦亡，为脓毒症的治疗提供了新治疗靶点；证实了PINK1-PARK2依赖的自噬降解线粒体铁代谢相关蛋白抑制K-RAS相关胰腺癌的发生发展，对临床探究胰腺癌治疗提供了新的研究靶点；阐明了SQSTM1-INSR轴的激活参与促进小鼠脓毒症和感染性休克的病理过程，可作为开发脓毒症治疗方法的靶点，研究具有重要的临床应用价值。