Role of IKK alpha in lung cancer development

Division Of Basic Sciences - Nci

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Abstract

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 IkB kinase alpha (IKKa), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKKa expression affects the TME. Here, we report that low IKKa expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cells (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 IKKa activity enhances formation of a pro-tumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC. This study reveals that impaired IKKa expression or activity in lung cancer enhances differentiation of pro-tumorigenic Treg cells through a TNF/TNFR2/NF-kB 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 new targets for the generation of TME-modifying therapies.