Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade.
Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade.
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DOI：
10.1016/j.jtho.2017.04.017
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Wong KK
中科院分区：
文献类型：
--
作者：
Akbay EA;Koyama S;Liu Y;Dries R;Bufe LE;Silkes M;Alam MM;Magee DM;Jones R;Jinushi M;Kulkarni M;Carretero J;Wang X;Warner-Hatten T;Cavanaugh JD;Osa A;Kumanogoh A;Freeman GJ;Awad MM;Christiani DC;Bueno R;Hammerman PS;Dranoff G;Wong KK
促炎细胞因子白介素17A(IL-17A)在部分肺癌患者体内过度表达。我们假设IL-17A促进促肿瘤形成的炎症表型，并抑制抗肿瘤免疫反应。我们产生了表达条件IL-17A等位基因和条件KrasG12D的双转基因小鼠，并进行了小鼠肺的免疫表型、生存分析和使用阻断PD-1或IL6的抗体或耗尽中性粒细胞的治疗研究。为了支持临床前的发现，我们分析了人类基因表达数据集和免疫图谱患者肺肿瘤。IL-17中的肿瘤：与KrasG12D相比，KrasG12D小鼠生长更快，导致存活时间显著缩短。IL-6、G-CSF、MFG-E8、CXCL1在IL17：KRAS小鼠肺组织中升高。时程分析显示，与KrasG12D相比，IL17：KrasG12D组小鼠肿瘤相关中性粒细胞(TANs)显著升高，淋巴细胞募集显著减少。在治疗研究中，PD-1阻断对IL-17：KrasG12D肿瘤无效。相反，在IL17：KrasG12D肿瘤中，用抗Ly-6G抗体阻断IL-6或耗尽中性粒细胞会导致与T细胞激活相关的临床反应。在KRAS突变肺癌患者的肿瘤中，我们发现高水平的IL-17A和集落刺激因子(CSF3)，以及高中性粒细胞和低T细胞数量之间存在显著的相关性。在这里，我们表明，在没有额外突变的情况下，单一细胞因子IL-17A的增加可以通过促进炎症来促进肺癌的生长，炎症有助于抵抗PD-1阻断，并使肿瘤对细胞因子/中性粒细胞耗竭敏感。
Proinflammatory cytokine Interleukin (IL)-17A (IL-17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a pro-tumorigenic inflammatory phenotype, and inhibits anti-tumor immune responses. We generated bi-transgenic mice expressing a conditional IL-17A allele along with conditional KrasG12D and performed immune phenotyping of mouse lungs, survival analysis, and treatment studies with antibodies either blocking PD-1 or IL6, or depleting neutrophils. To support preclinical findings, we analyzed human gene expression datasets and immune profiled patient lung tumors. Tumors in IL-17:KrasG12D mice grew more rapidly, resulting in a significantly shorter survival as compared to KrasG12D. IL-6, G-CSF, MFG-E8, and CXCL1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that tumor-associated neutrophils (TANs) were significantly elevated, and lymphocyte recruitment was significantly reduced in IL17:KrasG12D mice as compared to KrasG12D. In therapeutic studies PD-1 blockade was not effective in treating IL-17:KrasG12D tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:KrasG12D tumors resulted in a clinical response associated with T cell activation. In tumors from lung cancer patients with KRAS mutation we found a correlation among higher levels of IL-17A and the colony stimulating factor (CSF3), and a significant correlation among high neutrophil and lower T cell numbers. Here we show that an increase in a single cytokine, IL-17A, without additional mutations, can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD-1 blockade and sensitizes tumors to cytokine/neutrophil depletion.
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