p53-Mediated Tumor Immune Surveillance

 描述(申请人提供)：我们的研究重点是了解肿瘤发生的多步骤过程以及抑制肿瘤形成和进展的机制。我们已经从基因工程小鼠中开发出系统，以揭示和解构在人类癌症中常见突变的肿瘤抑制基因的作用时间和作用机制。我们的研究重点是肺腺癌，这是一种与预后不良相关的常见恶性肿瘤。此外，我们关注的是P53肿瘤抑制基因，因为它是这种癌症类型中最常见的突变基因。我们采用了一种策略，允许在已建立的小鼠肺腺癌中对P53作用进行时间控制，从而允许我们确定在这些癌症中随后发生在P53作用上的相关生物学程序。我们已经确定了一种需要自然杀伤细胞的非癌细胞自主肿瘤消退计划。我们的创新策略和独特的体内和细胞培养系统使我们能够询问由P53调控的特定分子在癌症中的作用，以及自然杀伤细胞在介导肿瘤消退时的生理反应。我们的目标是从机械上定义这一肿瘤抑制途径。这些见解将对未来旨在开发杀瘤自然杀伤细胞的工作具有重要意义，这些细胞可用作基于细胞的抗癌疗法。

 DESCRIPTION (provided by applicant): Our research is focused on understanding the multistep process of tumorigenesis and the mechanisms that suppress tumor formation and progression. We have developed systems from genetically engineered mice to uncover and deconstruct the timing and mechanism of action for tumor suppressor genes commonly mutated in human cancers. Our work here focuses on a lung adenocarcinoma, a common malignancy associated with poor prognosis. Additionally, we focus on the p53 tumor suppressor as it is the most frequently mutated gene in this cancer type. We employ a strategy that allows the temporal control over p53 actions in established murine lung adenocarcinomas that allows us to determine the relevant biological programs that ensue upon p53 action in these cancers. We have identified a non-cancer cell autonomous program of tumor regression that requires natural killer cells. Our innovative strategy and unique in vivo and cell culture systems afford us the ability to interrogate the roles of specific molecules regulated by p53 in the cancer and the physiological response of natural killer cells as they mediate tumor regression. Our goal here is to mechanistically define this tumor suppressive pathway. These insights will be important for future work aimed at developing tumoricidal natural killer cells that could be used as a cell-based anti- cancer therapy.