Abstract
The role of the tumour microenvironement (TME) in cancer progression and resistance to therapies is now widely recognized. The most prominent non-immune cell type in the microenvironment of oral cancer (OSCC) is cancer-associated fibroblasts (CAF). Although CAF are a poorly characterised and heterogenous cell population, those with an “activated” myofibroblastic phenotype have been shown to support OSCC progression, promoting growth, invasion and numerous other “hallmarks of malignancy.” CAF also confer broad resistance to different types of therapy, including chemo/radiotherapy and EGFR inhibitors; consistent with this, CAF-rich OSCC are associated with poor prognosis. In recent years, much CAF research has focused on their immunological role in the tumour microenvironment, showing that CAF shield tumours from immune attack through multiple mechanisms, and particularly on their role in promoting resistance to anti-PD-1/PD-L1 checkpoint inhibitors, an exciting development for the treatment of recurrent/metastatic oral cancer, but which fails in most patients. This review summarises our current understanding of CAF subtypes and function in OSCC and discusses the potential for targeting these cells therapeutically.
Highlights
The search for novel therapies has focused on tumour cells, attempting to inhibit oncogenic pathways that drive tumour progression; targeting the EGFR pathway for example
Macrophages and cancer stem cells have been highlighted as potential myofibroblastic CAF (myCAF) precursors [1, 10, 11], and it remains unclear whether cell of origin affects the final myCAF phenotype
This study identified two cancer-associated fibroblasts (CAF) populations; CAF-N, motile fibroblasts whose transcriptome and secretome were more similar to normal fibroblasts, and CAF-D subpopulation, which had a more divergent expression pattern and secreted high levels of TGF-β1
Summary
The search for novel therapies has focused on tumour cells, attempting to inhibit oncogenic pathways that drive tumour progression; targeting the EGFR pathway for example. Such targeted therapies can produce dramatic initial results, acquired resistance, where tumours progress after initial response, seems an almost inevitable consequence of this approach. Following the success of anti-PD-1/PD-L1 (programmed cell death protein 1/programmed death ligand 1) checkpoint immunotherapy, there has been a realisation that a tumour is a complex mixture of different cell types that interact to promote tumour progression, and this has generated significant interest in developing therapies that target the tumour microenvironment (TME) [1]
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