IKKα-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines.
IKKα-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines.
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DOI：
10.1073/pnas.2120956119
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发表时间：
2022-02-08
影响因子：
11.1
通讯作者：
Hu Y
中科院分区：
文献类型：
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作者：
Song NY;Li X;Ma B;Willette-Brown J;Zhu F;Jiang C;Su L;Shetty J;Zhao Y;Shi G;Banerjee S;Wu X;Tran B;Nussinov R;Karin M;Hu Y
本研究表明，IKKα在肺癌中的表达或活性受损，可通过TNF/TNFR2/NF-κB信号通路在人和小鼠肺ADC中促进致瘤性Treg细胞的分化。缺乏Treg细胞诱导所需的一种分子可抑制肺ADC的发展。因此，干扰这种特殊Treg分化的成分为tme修饰疗法的产生提供了靶标。肿瘤微环境（tumor microenvironment， TME）为肿瘤治疗提供了潜在靶点。然而，来自癌细胞的信号如何影响肿瘤导向免疫在很大程度上是未知的。编码IκB激酶α (IKKα)的CHUK位点缺失与肺腺癌（ADC）患者生存率降低相关，并促进krasg12d启动的ADC在小鼠中的发展，但IKKα表达降低如何影响TME尚不清楚。在这里，我们报道了IKKα在人和小鼠肺ADC细胞中的低表达与单核细胞源性巨噬细胞和调节性T细胞（Treg）评分升高以及巨噬细胞招募和Treg诱导细胞因子（CSF1, CCL22， TNF和IL-23A）编码基因转录升高相关。这些细胞因子通过刺激骨髓中单核细胞来源的巨噬细胞的募集，并强化TNF/TNFR2/c-Rel信号级联，刺激Treg的产生，从而促进肺ADC的进展。CD4+ T细胞或单核细胞源性巨噬细胞中TNFR2、c-Rel或TNF的消耗可抑制Treg的产生和肺肿瘤的发生。Treg耗竭也能减缓癌变。总之，降低的癌细胞IKKα活性通过其成分可能作为kras启动的肺ADC的治疗靶点的途径增强了致瘤性TME的形成。
This study reveals that impaired IKKα expression or activity in lung cancer enhances differentiation of protumorigenic Treg cells through a TNF/TNFR2/NF-κB signaling pathway in both human and mouse lung ADC. Depletion of one of the molecules that are required for Treg cell induction represses lung ADC development. Thus, the components that interfere with this particular Treg differentiation provide targets for the generation of TME-modifying therapies. The tumor microenvironment (TME) provides potential targets for cancer therapy. However, how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus, coding for IκB kinase α (IKKα), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKKα expression affects the TME. Here, we report that low IKKα expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cell (Treg) scores and elevated transcription of genes coding for macrophage-recruiting and Treg-inducing cytokines (CSF1, CCL22, TNF, and IL-23A). By stimulating recruitment of monocyte-derived macrophages from the bone marrow and enforcing a TNF/TNFR2/c-Rel signaling cascade that stimulates Treg generation, these cytokines promote lung ADC progression. Depletion of TNFR2, c-Rel, or TNF in CD4+ T cells or monocyte-derived macrophages dampens Treg generation and lung tumorigenesis. Treg depletion also attenuates carcinogenesis. In conclusion, reduced cancer cell IKKα activity enhances formation of a protumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC.
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影响因子：
32.4
作者：
Joshi NS;Akama-Garren EH;Lu Y;Lee DY;Chang GP;Li A;DuPage M;Tammela T;Kerper NR;Farago AF;Robbins R;Crowley DM;Bronson RT;Jacks T
通讯作者：
Jacks T
影响因子：
64.8
作者：
Lawrence, T;Bebien, M;Karin, M
通讯作者：
Karin, M
影响因子：
64.8
作者：
Anest, V;Hanson, JL;Baldwin, AS
通讯作者：
Baldwin, AS
影响因子：
10.9
作者：
Cannarile MA;Weisser M;Jacob W;Jegg AM;Ries CH;Rüttinger D
通讯作者：
Rüttinger D
影响因子：
64.8
作者：
通讯作者：
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