Roles of cancer associated fibroblasts in squamous cell carcinoma
Thesis or Dissertation
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Cancer associated fibroblasts (CAFs) play a key role in the tumour microenvironment (TME) of squamous cell carcinoma. Influenced by cues from cancer cells, CAFS remodel the extracellular matrix and secrete cytokines and chemokines. Both processes can modulate the effect of the immune infiltrate on the tumour. Using bioinformatic analysis of available datasets I showed that CAFs are correlated with an immunosuppressive environment in squamous cell carcinoma. To enquire into the mechanisms of this process I studied the interaction of cancer cells and CAFs at the tumour boundary through a co-culture model. Direct cancer cell-CAF interaction leads to production of interferon (IFN) type I and interferon stimulated genes (ISGs). The underlying mechanism is the cytoplasmic transfer of cGAMP from genetically unstable cancer cells to CAFs. Upregulation of ISGs conferred resistance to oncolytic virus therapy both in vitro and in vivo. Other cytokines unrelated to IFN, such as CSF2, IL6 and IL8 are also upregulated by cancer cell-CAF contact. I developed a model to study the influence of CAF-cancer cell interaction in the migration of immune cells at the tumour boundary. The motility and persistence of T-cells and monocytes is influenced by CAFs, especially in the interface between cancer cells and fibroblasts. I utilized a syngeneic murine oral squamous carcinoma model to explore further the interaction between immune cells, cancer cells and CAFs. MOC1 cells were derived from oral pouch of mice from C57/BI6 background by treatment with a carcinogenic and they are subjected to immune-surveillance in immunocompetent mice. Co-injection of CAFs helped overcome immune control. Targeting the immunosuppressive effects of CAFs could help improve the results of immunotherapy in patients with squamous cell carcinoma.
Carcinoma, Squamous Cell
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Institute of Cancer Research (University Of London)