Details

Autor(en) / Beteiligte

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

Titel

Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche

Ist Teil von

• Cell, 2016-08, Vol.166 (5), p.1117-1131.e14

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] [Display omitted] •PHD proteins function redundantly as oxygen sensors in T cells•T-cell-intrinsic expression of PHD proteins maintains immune tolerance in the lung•PHD proteins support cancer metastasis to the lung•Blockade of T-cell-intrinsic PHD proteins promotes anti-tumor immunity PHD-protein-mediated oxygen sensing by T cells creates an immunoenvironment in the lung that facilitates the establishment of cancer metastasis.