Genetics and Biology of Metastatic Colorectal Cancer

摘要/总结 该提案旨在剖析致癌 KRAS (Kras*) 其电路在控制 CRC 免疫中的作用 生物学的目标是阐明对 CRC 患者进行检测的有效治疗策略。一个数组 在我们的小鼠模型中比较 Kras*“开启”与 Kras*“关闭”状态的分子和病理生物学分析 人类 CRC 揭示 Kras* 驱动并维持侵袭性和转移性疾病，其中 Kras* 表达与骨髓源性抑制细胞 (MDSC) 的显着增加和骨髓源性抑制细胞 (MDSC) 的减少相关 杀伤性T细胞。初步机制研究表明 Kras* 激活 TGFβ，进而抑制 IRF2（主要干扰素调节因子），导致干扰素反应受到抑制。干扰素 网络通常发挥促进抗肿瘤反应的作用。因此，我们本研究的总体目标是评估 两个假设：(1) Kras*/TGFβ 介导的 IRF2 抑制会产生免疫抑制性肿瘤 促进癌症进展的微环境，以及 (2) Kras* 驱动的免疫抑制可能提供 大多数 CRC 中观察到的对免疫检查点阻断 (ICB) 疗法的从头耐药性的基础 患者。为了实现这些目标，我们提出以下具体目标： 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 TGFβ 的作用机制 抑制 IRF2，并确定 Kras* 驱动的 CRC 中 IRF2 调节的免疫回路，这可能有助于 免疫抑制肿瘤微环境促进癌症进展。在目标 3 中，我们将调查 CRC 中关键 Kras* 调控靶点的中和是否可以逆转免疫原发性耐药 检查点阻断疗法。总的来说，该提案旨在确定新颖的组合以改善 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.