Abstract
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.
Publication types
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Antigens, Neoplasm / immunology
- Cancer Vaccines / administration & dosage
- Cancer Vaccines / immunology
- Carcinoma, Lewis Lung / immunology*
- Carcinoma, Lewis Lung / pathology
- Carcinoma, Lewis Lung / therapy
- Carcinoma, Pancreatic Ductal / immunology*
- Carcinoma, Pancreatic Ductal / pathology
- Cell Hypoxia
- Cell Line, Tumor
- Cell Survival
- Endopeptidases
- Gelatinases / metabolism*
- Immune Tolerance*
- Interferon-gamma / immunology
- Interferon-gamma / metabolism
- Membrane Proteins / metabolism*
- Mice
- Mice, Transgenic
- Necrosis
- Neoplasm Transplantation
- Serine Endopeptidases / metabolism*
- Stromal Cells / immunology*
- Stromal Cells / metabolism
- Tumor Microenvironment / immunology*
- Tumor Necrosis Factor-alpha / immunology
- Tumor Necrosis Factor-alpha / metabolism
Substances
- Antigens, Neoplasm
- Cancer Vaccines
- Membrane Proteins
- Tumor Necrosis Factor-alpha
- Interferon-gamma
- Endopeptidases
- Serine Endopeptidases
- fibroblast activation protein alpha
- Gelatinases