Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA.
Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
Nat Commun. 2021 Mar 5;12(1):1482. doi: 10.1038/s41467-021-21736-w.
Immune evasion is a hallmark of KRAS-driven cancers, but the underlying causes remain unresolved. Here, we use a mouse model of pancreatic ductal adenocarcinoma to inactivate KRAS by CRISPR-mediated genome editing. We demonstrate that at an advanced tumor stage, dependence on KRAS for tumor growth is reduced and is manifested in the suppression of antitumor immunity. KRAS-deficient cells retain the ability to form tumors in immunodeficient mice. However, they fail to evade the host immune system in syngeneic wild-type mice, triggering strong antitumor response. We uncover changes both in tumor cells and host immune cells attributable to oncogenic KRAS expression. We identify BRAF and MYC as key mediators of KRAS-driven tumor immune suppression and show that loss of BRAF effectively blocks tumor growth in mice. Applying our results to human PDAC we show that lowering KRAS activity is likewise associated with a more vigorous immune environment.
免疫逃避是 KRAS 驱动癌症的一个标志，但潜在的原因仍未得到解决。在这里，我们使用 CRISPR 介导的基因组编辑在小鼠胰腺导管腺癌模型中失活 KRAS。我们证明，在晚期肿瘤阶段，对 KRAS 促进肿瘤生长的依赖性降低，表现在抑制抗肿瘤免疫上。KRAS 缺陷细胞在免疫缺陷小鼠中仍保留形成肿瘤的能力。然而，在同基因野生型小鼠中，它们无法逃避宿主免疫系统，引发强烈的抗肿瘤反应。我们发现归因于致癌 KRAS 表达的肿瘤细胞和宿主免疫细胞的变化。我们确定 BRAF 和 MYC 是 KRAS 驱动的肿瘤免疫抑制的关键介质，并表明 BRAF 的缺失有效地阻止了小鼠的肿瘤生长。将我们的结果应用于人类 PDAC，我们表明降低 KRAS 活性同样与更活跃的免疫环境相关。
