Therapeutic cancer vaccines are ineffective even though they cause expansion of tumor 'specific T cells, because these T cells are inhibited by the tumor stromal microenvironment in both humans and mice. The Fearon lab depleted stromal cells expressing fibroblast activation protein-alpha (FAP), which are found in all human carcinomas, by administering diphtheria toxin (DT) to a mouse transgenic for the human DT receptor driven by fap transcriptional regulatory elements. This caused frank necrosis of LL2/OVA tumors, supporting the proposed detrimental role for the FAP+ cell in the response to therapeutic vaccines ' work now in press with Science.
This research next aims to determine the signals that cause the development of the FAP+ stromal cell, and the means by which the FAP+ cell causes local immunosuppression. An additional interesting aspect of this cell type is that it exists in normal mice and regulates hematopoiesis and appetite, the former probably via forming the osteoblastic niche and the latter by unknown means.
Pharmacological interruption of either of these processes would be predicted to enhance the efficacy of therapeutic cancer vaccines. Depletion of FAP+ stromal cells also controls the growth of pancreatic ductal adenocarcinomas in the KPC mouse; interesting because this is the best murine model of a human adenocarcinoma. The focus on this stromal cell was prompted by clinical studies of the occurrence of FAP+ cells in human cancers, an autoimmune disease (RA), and chronic tissue repair (cirrhosis).
Therefore, they represent direct interventional extensions of clinical research that was limited initially to correlative analyses in mouse models, but now will be translated back to the clinic.
