Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-[alpha]

Vaccination with tumor-specific antigens is one of several attempted therapies seeking to harness the immune system, but -- unfortunately -- this strategy has been unsuccessful, possibly because of the immunosuppressive properties of the tumor microenvironment. Kraman et al. (p. 827; see the Perspective by Schreiber and Rowley ) have identified immunosuppressive cells of mesenchymal origin in mice comprising 2% of the tumor stromal cell population. They were identified by expression of the fibroblast activation protein-α. Deletion of these cells in lung or pancreatic cancers in mice allowed successful therapeutic vaccination against the tumors, which was dependent on the adaptive immune system and the cytokines interferon-γ and tumor necrosis factor-α. These findings reveal that multiple cell types contribute to the immunosuppressive tumor microenvironment and will inform therapeutic cancer vaccine design. [PUBLICATION 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 ABSTRACT]