David Clever, Rahul Roychoudhuri, Michael G. Constantinides, Michael H. Askenase, Madhusudhanan Sukumar, Christopher A. Klebanoff, Robert L. Eil, Heather D. Hickman, Zhiya Yu, Jenny H. Pan, Douglas C. Palmer, Anthony T. Phan, John Goulding, Luca Gattinoni, Ananda W. Goldrath, Yasmine Belkaid, Nicholas P. Restifo
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-γ-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.