Genetics and Biology of Metastatic Colorectal Cancer

摘要/概要 该建议旨在剖析致癌KRAS（Kras*）及其电路在控制CRC免疫中的作用， 生物学的目标是阐明有效的治疗策略，用于在CRC患者中进行测试。的阵列 在我们的小鼠模型中比较Kras*“开”与Kras*“关”状态的分子和病理生物学分析， 人类CRC已经揭示Kras* 驱动并维持侵袭性和转移性疾病，Kras* 表达与髓源性抑制细胞（MDSC）的显著增加和髓源性抑制细胞（MDSC）的减少相关。 杀手T细胞初步的机制研究表明，Kras* 激活TGFβ，反过来抑制 IRF 2（干扰素调节因子），导致干扰素反应的抑制。干扰素 正常情况下，网络的功能是促进抗肿瘤反应。因此，本研究的总体目标是评估 两种假设：（1）Kras*/TGFβ介导的IRF 2抑制产生免疫抑制性肿瘤 （2）Kras* 驱动的免疫抑制可能提供一个促进癌症进展的微环境， 在大多数CRC中观察到的免疫检查点阻断（ICB）治疗新发耐药的基础 患者为了实现这些目标，我们提出了以下具体目标：在目标1中，我们将描述 利用我们的新型CRC小鼠模型，在原发性CRC中由Kras* 驱动的免疫抑制细胞亚型，以及 评估Kras* 突变对MDSC和TAM活性的影响，以鉴定信号分子 控制这些肿瘤的免疫抑制在目标2中，我们将确定TGFβ 抑制IRF 2，并确定Kras* 驱动的CRC中由IRF 2调节的免疫回路， 免疫抑制肿瘤微环境使癌症进展。在目标3中，我们将研究 CRC中关键Kras* 调节靶点的中和是否可以逆转免疫原性耐药， 检查点阻断疗法总的来说，这项建议旨在确定新的组合，以改善 Kras* CRC中的ICB敏感性。

Abstract/Summary This proposal aims to dissect the actions of oncogenic KRAS (Kras*) its circuitry in controlling CRC immune biology with the goal of illuminating effective therapeutic strategies for testing in CRC patients. An array of molecular and pathobiological analyses comparing Kras* `on' versus Kras* `off' states in our mouse model of human CRC has revealed that Kras* drives and maintains invasive and metastatic disease, with Kras* expression correlating with a significant increase in myeloid derived suppressor cells (MDSCs) and decrease in killer T-cells. Preliminary mechanistic studies have shown that Kras* activates TGFβ, which in turn represses IRF2 (a master interferon regulatory factor), resulting in suppression of interferon response. The interferon network normally functions to promote anti-tumor responses. Thus, our overall goal in this study is to evaluate two hypotheses: (1) that Kras*/TGFβ-mediated repression of IRF2 creates an immune suppressive tumor microenvironment enabling cancer progression, and (2) that Kras*-driven immune suppression may provide a basis for the de novo resistance to immune checkpoint blockade (ICB) therapy observed in the majority of CRC patients. To achieve these goals, we propose the following Specific Aims: In Aim 1, we will characterize the immune suppressive cell subtypes driven by Kras* in primary CRC utilizing our novel CRC mouse model, and evaluate the effects of Kras* mutation on MDSC and TAM activities to identify the signaling molecules governing immune suppression in these tumors. In Aim 2, we will determine the mechanism by which TGFβ suppresses IRF2, and identify the immune circuits regulated by IRF2 in Kras*-driven CRC that may contribute to an immune suppressive tumor microenvironment enabling cancer progression. In Aim 3, we will investigate whether the neutralization of key Kras*-regulated targets in CRC can reverse primary resistance to immune checkpoint blockade therapy. Collectively, this proposal aims to identify novel combinations to improve the ICB sensitivity in Kras* CRC.