BioProject

Cancer cells must evade immune responses at distant sites to establish metastases. More...

Cancer cells must evade immune responses at distant sites to establish metastases. The lung is a frequent site for metastasis. We hypothesized that lung-specific immunoregulatory mechanisms create an immunologically permissive environment for tumor colonization. We found that T cell-intrinsic expression of the oxygen-sensing prolyl-hydroxylase (PHD) proteins is required to maintain local tolerance against innocuous antigens in the lung, but powerfully licenses colonization by circulating tumor cells. PHD proteins limit pulmonary type helper (Th)-1 responses, promote CD4+-regulatory T (Treg) cell induction, and restrain CD8+ T cell effector function. Tumor colonization is accompanied by PHD protein-dependent induction of pulmonary Treg cells and suppression of IFN-g-dependent tumor clearance. T cell-intrinsic deletion or pharmacological inhibition of PHD proteins limits tumor colonization of the lung and improves the efficacy of adoptive cell transfer immunotherapy. Collectively, PHD proteins function in T cells to coordinate distinct immunoregulatory programs within the lung that are permissive to cancer metastasis. Overall design: RNA expression was measured by RNA-Seq at day 4 following stimulation of naïve FACS-sorted CD4+ T cells with anti-CD3 and anti-CD28 antibodies in the presence of indicated doses of TGF-b. Gene expression was analysed separately in control Cd4Cre (WT) and Egln1fl/fl Egln2fl/fl Egln3fl/fl Cd4Cre (tKO) cells, or in cells treated with the pharmacological PHD inhibitor dimethyloxaloylglycine (DMOG) and control vehicle-treated cells. Less...