Role of IKK alpha in lung cancer development

Division Of Basic Sciences - Nci

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Abstract

Immunosuppressive tumor microenvironment is a major driver for carcinogenesis. However, how the signaling pathways derived from cancer cells induce immunosuppression remains to be fully investigated. Deletions of the CHUK locus, which encodes IKKa, are correlated with a reduced survival among lung adenocarcinoma (ADC) patients as well as promote mouse lung ADC development in association with excessive ROS. Here, we reveal that CHUK/IKKa reduction in human and mouse lung ADCs is associated with increased macrophage and Treg cell scores and the important molecules required for macrophage and Treg cell development by upregulating the transcription of CSF1, CCL22, TNF, and IL-23A genes via lifting the DNA-sequence-specific bindings. We demonstrate that macrophages in a number- and ROS-dependent manner mediate Treg cell induction from CD4 T cells through a ROS/TNF/TNFRSF1B/c-Rel pathway. Silencing one of these transducers in this signaling, or depleting macrophage or Treg cells attenuates immunosuppressive responses and lung carcinogenesis. ROS or TNF enhances Treg induction from CD4 T cells through TNFRSF1B to c-Rel activity whereas TNFRSF1B ablation in CD4 T cells blocks ROS- and TNF-mediated Treg induction. Thus, TNFRSF1B connects cancer cells and macrophages to promote Treg cell induction and advance lung carcinogenesis. Consistently, human lung ADC patients expressing reduced CHUK and increased TNFRSF1B die earlier than patients expressing diploid CHUK and TNFRSF1B. These defined molecules emerge as therapeutic targets for lung cancer as well as IKKa serves as a surveillant restraining immunosuppressive responses.