IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties.
IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties.
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DOI：
10.1158/2326-6066.cir-17-0655
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发表时间：
2018-07
影响因子：
10.1
通讯作者：
Moghaddam SJ
中科院分区：
文献类型：
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作者：
Khosravi N;Caetano MS;Cumpian AM;Unver N;De la Garza Ramos C;Noble O;Daliri S;Hernandez BJ;Gutierrez BA;Evans SE;Hanash S;Alekseev AM;Yang Y;Chang SH;Nurieva R;Kadara H;Chen J;Ostrin EJ;Moghaddam SJ
体细胞KRAS突变是肺癌中最常见的致癌变异，与预后不良有关。在kras诱导的肺癌小鼠模型CC-LR中，我们之前通过激活NF-κB途径，以及诱导白细胞介素6 （il - 6）和产生il - 17的CD4+ t辅助细胞反应，证明了炎症在肺肿瘤发生中的作用。IL22是一种由CD4+和γδ T细胞分泌的效应分子，我们之前发现在CC-LR小鼠中表达。IL22主要通过STAT3通路发出信号，被认为只作用于上皮细胞上表达基础IL22受体（IL22R）的非造血细胞。在这里，我们发现IL22R1在KRAS突变型肺腺癌患者中较高的表达是无复发生存率差的独立指标。然后，我们发现CC-LR小鼠（CC-LR/IL22KO小鼠）的Il22基因消融导致肿瘤数量和大小显著减少。这伴随着肿瘤细胞增殖、血管生成和STAT3激活的显著降低。il - 22消融术还与肺浸润性炎症细胞和促肿瘤炎性细胞因子表达的显著减少有关。相反，这伴随着抗肿瘤Th1和细胞毒性CD8+ T细胞反应的增加，同时抑制促肿瘤免疫抑制T调节细胞反应。在CC-LR/IL22KO小鼠中，我们发现核心干细胞基因的表达和原型SPC+CCSP+干细胞的数量显著降低。因此，我们得出结论，IL22通过在上皮/肿瘤细胞中驱动促肿瘤炎症微环境，促进Kras突变体的肺肿瘤发生，并伴有增生、血管生成和干性相关提示。
Somatic KRAS mutations are the most common oncogenic variants in lung cancer and are associated with poor prognosis. Using a Kras–induced lung cancer mouse model, CC-LR, we previously showed a role for inflammation in lung tumorigenesis through activation of the NF-κB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4+ T-helper cell response. IL22 is an effector molecule secreted by CD4+ and γδ T cells that we previously found to be expressed in CC-LR mice. IL22 mostly signals through the STAT3 pathway and is thought to act exclusively on non-hematopoietic cells with basal IL22 receptor (IL22R) expression on epithelial cells. Here, we found that higher expression of IL22R1 in patients with KRAS mutant lung adenocarcinoma was an independent indicator of poor recurrence-free survival. We then showed that genetic ablation of Il22 in CC-LR mice (CC-LR/IL22KO mice) caused a significant reduction in tumor number and size. This was accompanied by significantly lower tumor cell proliferation, angiogenesis, and STAT3 activation. Il22 ablation was also associated with significant reduction in lung-infiltrating inflammatory cells and expression of pro-tumor inflammatory cytokines. Conversely, this was accompanied with increased antitumor Th1 and cytotoxic CD8+ T cell responses, while suppressing the pro-tumor immunosuppressive T regulatory cell response. In CC-LR/IL22KO mice, we found significantly reduced expression of core stemness genes and the number of prototypical SPC+CCSP+ stem cells. Thus, we conclude that IL22 promotes Kras mutant lung tumorigenesis by driving a pro-tumor inflammatory microenvironment with proliferative, angiogenic, and stemness contextual cues in epithelial/tumor cells.