Cell子刊:KRAS突变驱动结直肠癌中的免疫治疗耐药性
  • 携带G12D突变的KRAS(KRAS∗)通过IFN-γ和IFN-α信号通路促进结直肠癌的免疫抑制;
  • 2型干扰素调节因子(IRF2)是KRAS∗介导的免疫抑制的关键下游靶点;
  • KRAS∗通过抑制IRF2促进CXCL3的表达,后者可结合骨髓源性抑制细胞(MDSC)上的CXCR2,以促进MDSC向肿瘤微环境中的迁移与浸润;
  • 增加IRF2的表达或抑制CXCR2,可克服结直肠癌小鼠模型对抗PD-1药物的耐药;
  • 在结直肠癌患者中,IRF2的表达水平越高,对抗PD-1治疗的应答越强。
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KRAS的G12D突变可对免疫检查点抑制剂治疗产生耐药性,但其机制尚未明确。《Cancer Cell》上发表的一项最新研究发现,该突变可通过抑制2型干扰素调节因子(IRF2),促进骨髓源性抑制细胞(MDSC)向肿瘤微环境中的浸润,从而产生免疫抑制,介导了对免疫检查点抑制剂治疗的耐药性。进一步研究发现,IRF2的表达量越高,结直肠癌患者对PD-1单抗治疗的响应越好,提示KRAS-IRF2轴或可在肿瘤精准医疗中发挥重要作用。
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Cancer Cell [IF:38.585]

KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer

KRAS-IRF2轴驱动结直肠癌中的免疫抑制和对免疫治疗的耐药性

10.1016/j.ccell.2019.02.008

2019-03-21, Article

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The biological functions and mechanisms of oncogenic KRAS G12D (KRAS ∗) in resistance to immune checkpoint blockade (ICB) therapy are not fully understood. We demonstrate that KRAS ∗ represses the expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS ∗-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration to the tumor microenvironment. Anti-PD-1 resistance of KRAS ∗-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. Colorectal cancer (CRC) showing higher IRF2 expression exhibited increased responsiveness to anti-PD-1 therapy. The KRAS ∗-IRF2-CXCL3-CXCR2 axis provides a framework for patient selection and combination therapies to enhance the effectiveness of ICB therapy in CRC.

First Authors:
Wenting Liao

Correspondence Authors:
Y Alan Wang,Ronald A DePinho

All Authors:
Wenting Liao,Michael J Overman,Adam T Boutin,Xiaoying Shang,Di Zhao,Prasenjit Dey,Jiexi Li,Guocan Wang,Zhengdao Lan,Jun Li,Ming Tang,Shan Jiang,Xingdi Ma,Peiwen Chen,Riham Katkhuda,Krittiya Korphaisarn,Deepavali Chakravarti,Andrew Chang,Denise J Spring,Qing Chang,Jianhua Zhang,Dipen M Maru,Dean Y Maeda,John A Zebala,Scott Kopetz,Y Alan Wang,Ronald A DePinho

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