Treg cell by tumor-associated macrophage ROS and inflammatory signaling through T-cell NF-κB c-Rel drives pathogenesis of lung adenocarcinomas
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA548126 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9259158.fastq.gz | Fastqsanger.gz | |||
| SRR9259159.fastq.gz | Fastqsanger.gz |
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Project description: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.
2022-01-31 | GSE132460 | GEO
Project description:The outcome of cancer and autoimmunity is dictated by the recruitment and effector functions of CD4+ conventional T cells (Tconv cells). The NF-kappaB (NF-κB) family of transcription factors is implicated in different aspects of Tconv cell biology, but the cell-autonomous roles of NF-κB subunits are elusive. Here, we explored the contributions of canonical RelA and c-Rel subunits to Tconv function in health and disease. We found that RelA, rather than c-Rel, shaped the transcriptome of mouse and human Tconv cells at steady-state and was required for Tconv polarization toward the TH17 lineage in vitro. RelA-deficient mice were fully protected against neuro-inflammation in a mouse model of multiple sclerosis (MS), because of defective transition to a pathogenic TH17 gene expression program. In contrast, Tconv-restricted ablation of c-Rel, but not RelA, impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. c-Rel in Tconv cells was required for the response to PD-1-blockade therapy, and a c-Rel-dependent gene signature was correlated with better response and prognosis in anti-PD-1-treated patients. Our data demonstrate a division of labor between different subunits of the NF-κB pathway, paving the way for subunit-targeted immunotherapies.
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Project description:The outcome of cancer and autoimmunity is dictated by the recruitment and effector functions of CD4+ conventional T cells (Tconv cells). The NF-kappaB (NF-κB) family of transcription factors is implicated in different aspects of Tconv cell biology, but the cell-autonomous roles of NF-κB subunits are elusive. Here, we explored the contributions of canonical RelA and c-Rel subunits to Tconv function in health and disease. We found that RelA, rather than c-Rel, shaped the transcriptome of mouse and human Tconv cells at steady-state and was required for Tconv polarization toward the TH17 lineage in vitro. RelA-deficient mice were fully protected against neuro-inflammation in a mouse model of multiple sclerosis (MS), because of defective transition to a pathogenic TH17 gene expression program. In contrast, Tconv-restricted ablation of c-Rel, but not RelA, impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. c-Rel in Tconv cells was required for the response to PD-1-blockade therapy, and a c-Rel-dependent gene signature was correlated with better response and prognosis in anti-PD-1-treated patients. Our data demonstrate a division of labor between different subunits of the NF-κB pathway, paving the way for subunit-targeted immunotherapies.
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