Genetics and Biology of Metastatic Colorectal Cancer

摘要/摘要 这项建议旨在剖析致癌KRAS(Kras*)及其回路在控制CRC免疫中的作用 生物学，目的是阐明对结直肠癌患者进行检测的有效治疗策略。一组 Kras*‘on’与Kras*‘off’状态的分子和病理生物学分析比较 人类CRC揭示了Kras*与Kras*一起驱动和维持侵袭性和转移性疾病 髓系抑制细胞(MDSCs)的表达与MDSCs显著增加和MDSCs减少相关 杀手T细胞。初步的机制研究表明，kras*激活转化生长因子β，进而抑制 IRF2(一个主要的干扰素调节因子)，导致干扰素反应被抑制。干扰素 网络通常起到促进抗肿瘤反应的作用。因此，我们在本研究中的总体目标是评估 两个假设：(1)kras*/转化生长因子β介导的irf2抑制产生免疫抑制性肿瘤 促成癌症进展的微环境，以及(2)Kras*驱动的免疫抑制可能提供 大多数结直肠癌对免疫检查点阻断(ICB)治疗产生从头抵抗的基础 病人。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 利用我们新的结直肠癌小鼠模型，Kras*在原发结直肠癌中驱动免疫抑制细胞亚型，以及 评估Kras*突变对骨髓间充质干细胞和活性的影响以确定信号分子 控制这些肿瘤的免疫抑制。在目标2中，我们将确定转化生长因子β 抑制IRF2，并识别在Kras*驱动的CRC中受IRF2调控的可能起作用的免疫回路 导致癌症进展的免疫抑制肿瘤微环境。在目标3中，我们将调查 结直肠癌中Kras*调控的关键靶点的中和能否逆转对免疫的原发耐药性 关卡封锁疗法。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.