Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha.
The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein-α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.
Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, UK.
Matthew
M
Kraman
Paul J
PJ
Bambrough
James N
JN
Arnold
Edward W
EW
Roberts
Lukasz
L
Magiera
James O
JO
Jones
Aarthi
A
Gopinathan
David A
DA
Tuveson
Douglas T
DT
Fearon
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D010450:Endopeptidases; D018093:Gelatinases / Q000378:metabolism*; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D009368:Neoplasm Transplantation; D012697:Serine Endopeptidases / Q000378:metabolism*; D017154:Stromal Cells / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D000099167:Fibroblast Activation Protein Alpha
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D010450:Endopeptidases; D018093:Gelatinases; D007371:Interferon-gamma; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D014409:Tumor Necrosis Factor-alpha; D000099167:Fibroblast Activation Protein Alpha