Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche

• David Clever ; Rahul Roychoudhuri ^[1] ; Michael G. Constantinides ^[2]
  1. [1] Babraham Institute

     Babraham Institute

     Cambridge District, Reino Unido

     
  2. [2] National Institutes of Health

     National Institutes of Health

     Estados Unidos

     
• Localización: Cell, ISSN 0092-8674, Vol. 166, Nº. 5, 2016, págs. 1117-1131
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • 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.