IKKalpha-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines
Menée in vitro et à l'aide d'un modèle murin d'adénocarcinome du poumon, cette étude met en évidence un mécanisme par lequel une déficience de la kinase IKK alpha au niveau des cellules tumorales favorise le développement d'un microenvironnement immunosuppresseur en augmentant la production de cytokines qui stimulent la production de lymphocytes T régulateurs
This study reveals that impaired IKKα expression or activity in lung cancer enhances differentiation of protumorigenic Treg cells through a TNF/TNFR2/NF-κB 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 targets for the generation of TME-modifying therapies.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 IκB kinase α (IKKα), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKKα expression affects the TME. Here, we report that low IKKα 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 IKKα activity enhances formation of a protumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC.Tumor-associated macrophage data have been deposited in National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) from mouse lung adenocarcinoma-associated macrophages (GSE114501). Anonymized tumor-associated CD4 T cells and ChIP-seq data have been deposited in GEO from mouse lung adenocarcinoma-associated CD4 cells (GSE122419 and GSE132460). All other study data are included in the article and/or supporting information.