The Role of Mutant p53 in Regulating T-cell Immune Evasion in Pancreatic Adenocarcinoma and Other Cancers

项目概要/摘要 通过减弱T细胞上的内源性免疫检查点来利用患者的免疫系统， 导致了对多种肿瘤类型的显著的、持久的肿瘤排斥。尽管如此，胰腺导管腺癌 PDAC在很大程度上仍然对所有疗法（包括免疫疗法）具有抗性，导致其作为癌症的一种而臭名昭著。 最致命的恶性肿瘤，5年生存率为6%。为了设计PDAC的有效治疗方法， 重要的是了解PDAC逃避宿主免疫系统的机制。不像 对于免疫治疗应答的肿瘤类型如黑素瘤，PDAC是突变同质的，具有高达 75%的肿瘤具有肿瘤抑制基因p53的突变。p53缺失被充分描述为介导肿瘤 逃避凋亡和衰老。p53错义突变体（mtp 53）也获得功能获得性活性 与p53的野生型活性不同。临床前研究支持mtp 53介导肿瘤逃避免疫 通过调节先天性免疫效应物（包括NK细胞和巨噬细胞）进行监测。很少有研究 然而，已经完成了对mtp 53在改变适应性免疫效应物中的作用的研究，包括 细胞毒性T细胞理解mtp 53在介导PDAC中T细胞浸润和功能中的作用， 提供了一个新的框架，以了解和克服癌症免疫治疗的阻力。在这个项目中，我 将确定mtp 53的各种结构-功能类别是否影响PDAC肿瘤发生或肿瘤 通过影响T细胞功能来维持。我假设p53突变介导T细胞逃避， 在PDAC和其他肿瘤中介导的杀伤和免疫治疗，mtp 53类是重要的 这个过程中的因素。为了验证这一假设，我将确定p53肿瘤突变状态是否影响 PDAC中的T细胞浸润、表型和功能，使用新型PDAC鼠模型和流式细胞术， CyTOF、Caspase和细胞因子分泌测定，并确定p53突变状态是否影响 免疫检查点抑制剂的反应。随着这些目标的成功实现，我将确定p53是否 突变状态促进PDAC中T细胞介导的免疫逃逸。这些结果将阐明 mtp 53在肿瘤发生中的激活突变，鉴定出潜在的可靶向的下游效应子， mtp 53，并提供基本原理，研究mtp 53免疫调节PDAC和其他肿瘤类型。

Project Summary/Abstract Harnessing a patient’s immune system by attenuating endogenous immune checkpoints on T-cells has led to dramatic, durable tumor rejection for multiple tumor types. Nonetheless, pancreatic ductal adenocarcinoma (PDAC) remains largely resistant to all therapies, including immunotherapies, leading to its notoriety as one of the most lethal malignancies, with a 6% 5-year survival rate. To design efficacious treatments for PDAC, it is important to understand the mechanism by which PDAC escapes the host immune system. Unlike immunotherapy-responsive tumor types such as melanoma, PDAC is mutationally homogeneous, with up to 75% of tumors possessing mutations in the tumor suppressor p53. p53 loss is well-described to mediate tumor escape from apoptosis and senescence. p53 missense mutants (mtp53) also acquire gain-of-function activities distinct from p53’s wild-type activity. Pre-clinical studies support that mtp53 mediate tumor escape from immune surveillance by modulating innate immune effectors, including NK cells and macrophages. Few studies have been completed, however, investigating the role of mtp53 in altering adaptive immune effectors, including cytotoxic T-cells. Understanding the role of mtp53 in mediating T-cell infiltration and function in PDAC would provide a novel framework to understand and overcome resistance to cancer immunotherapy. In this project, I will determine whether various structure-function classes of mtp53 impact PDAC oncogenesis or tumor maintenance by impacting T-cell function. I hypothesize that p53 mutations mediate evasion of T-cell- mediated killing and immunotherapy in PDAC and other tumors, and that mtp53 class is an important factor in this process. To test this hypothesis, I will establish whether p53 tumor mutational status influences T-cell infiltration, phenotype, and functionality in PDAC, using novel PDAC murine models and flow cytometry, CyTOF, Caspase, and cytokine secretion assays, and determine whether p53 mutational status impacts response to immune checkpoint inhibitors. With the successful completion of these aims, I will ascertain if p53 mutational status promotes T-cell-mediated immune escape in PDAC. These results would elucidate the role of mtp53 activating mutations in tumorigenesis, identify potentially-targetable downstream effectors unique to mtp53, and provide rationale to investigate mtp53 immune-regulation in PDAC and other tumor types.