Investigating the fibroblast activation protein alpha expressing stromal cell in a spontaneous murine model of pancreatic adenocarcinoma
Jones, James Owain
University of Cambridge
School of Clinical Medicine
Doctor of Philosophy (PhD)
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Jones, J. O. (2013). Investigating the fibroblast activation protein alpha expressing stromal cell in a spontaneous murine model of pancreatic adenocarcinoma (Doctoral thesis). https://doi.org/10.17863/CAM.11736
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There is evidence from cancer patients and animal models that the immune system is able to recognise cancer cells. It is unclear whether tumours escape this immune surveillance by selection of non-immunogenic variants in a Darwinian process termed cancer immunoediting, or by the recruitment of immune suppressive cells to the tumour microenvironment. This distinction is important as it informs the best means of cancer immunotherapy. Our lab has previously demonstrated that a stromal cell marked by fibroblast activation protein alpha (FAP) mediates local immune suppression in transplantable tumour models. Such models however do not always reflect the biology of human cancer. The following work investigates whether FAP+ cells modulate the immune response in a more physiological spontaneous murine model of pancreatic ductal adenocarcinoma (PDA). CD8+ T cells from PDA bearing mice show reactivity against thei.r own tumour cells in ELISpot assays, indicating an ongoing response to tumour antigens. Relieving immune suppression by depletion of FAP+ cells might therefore be effective in this model. Depletion of FAP+ cells for one week results in immune dependent arrest of PDA growth, demonstrating that FAP+ cells are a critical component of immune suppression. These data imply that immunoediting of tumour antigens does not account for escape from immune surveillance in this model. A therapy that targets FAP+ cell dependent immune suppression may allow an existing immune response to control cancers. Based on marker expression FAP+ cells in PDA appear related to carcinoma associated fibroblasts. Whilst it was previously thought that FAP+ cells were restricted to sites of inflammation and tissue remodelling, others in the lab have shown that FAP+ cells are widely distributed in normal tissues. FAP+ cells were sorted from PDA and several normal tissues for RNA-seq analysis. The transcriptomic data suggests that FAP+ cells in normal tissues are highly similar: FAP+ cells in PDA are related but form a distinct subset. Of particular interest, FAP+ cells from PDA and normal tissues express myeloid chemokines. FAP may therefore mark a lineage of tissue resident cells that regulate inflammation.
This record's DOI: https://doi.org/10.17863/CAM.11736