IKKα-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines

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 I kappa B kinase a (IKK alpha), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKK alpha expression affects the TME. Here, we report that low IKK alpha 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 IKK alpha activity enhances formation of a protumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC.

Automated summary

The low expression of IKK alpha in lung adenocarcinoma cells is associated with increased monocyte-derived macrophages and regulatory T cells, as well as elevated levels of cytokines that recruit macrophages and induce Tregs. These cytokines stimulate the progression of lung adenocarcinoma by promoting the recruitment of macrophages and generating Tregs through TNF/TNFR2/c-Rel signaling cascade. Depletion of TNFR2, c-Rel, or TNF inhibits Treg generation and lung tumorigenesis.