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Treg cell by tumor-associated macrophage ROS and inflammatory signaling through T-cell NF-κB c-Rel drives pathogenesis of lung adenocarcinomas

ABSTRACT: IKKα, one subunit of the IKK complex composed of IKKα, IKKβ, and IKKγ (NEMO), is essential for canonical and noncanonical NF-κB pathways involved in the development of lymphoid organs, leukocytes, immunity, and epithelial organs. Deletions of the CHUK locus that encodes IKKα significantly reduce survival for both KRAS-mutation lung adenocarcinoma (ADC) patients and mice, but the question of whether IKKα regulates immune responses remains unanswered. Here, we show that tumor-IKKα reduction elicits an immunosuppressive tumor-microenvironment associated with macrophage and Treg cell induction, which are maintained through elevated reactive oxygen species (ROS) and cytokines important for macrophage and Treg cell development in human and mouse lung ADCs. Enhanced macrophage-ROS and inflammatory cytokine signaling, mediated by tumor-cell IKKα reduction, enforces Treg cell differentiation via a ROS/TNFα/TNFR2/c-Rel pathway in CD4 T-cells. The blockage of each crucial step, including ROS, macrophages, Treg cells, and TNFα/c-Rel, impairs lung ADC development. To explore the molecular mechanism, we performed ChIP-Seq to check some important immunoregulatory genes including TNF, IL-23A CSF1, and CCL22 were regulated transcriptionally by IKKα. Therefore, IKKα serves as a specific surveillant that suppresses immunosuppressive responses and antagonizes lung carcinogenesis in humans and mice.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132460 | GEO | 2022/01/31

REPOSITORIES: GEO

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2012-04-30 | E-GEOD-37655 | biostudies-arrayexpress

Treg cell by tumor-associated macrophage ROS and inflammatory signaling through T-cell NF-κB c-Rel drives pathogenesis of lung adenocarcinomas

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2014-08-25 | E-GEOD-43767 | biostudies-arrayexpress

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