Cancer-Associated Fibroblasts in Oral Cancer: A Current Perspective on Function and Potential for Therapeutic Targeting

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.

Integrated analysis of genome-wide DNA methylation and cancer-associated fibroblasts identified prognostic biomarkers and immune checkpoint blockade in lower grade gliomas

“…On the other hand, CAFs and extracellular matrices constitute the tumor immune escape initiation mechanism ( 13 ). In response to this problem, harnessing CAFs-related immunosuppressive stromal environment has been proposed to ameliorate the response to immune checkpoint inhibitors ( 14 , 15 ). However, whether CAFs are associated with the predictive value and immunotherapy of LGGs patients has not been elucidated.…”

Integrated single-cell and bulk RNA sequencing analyses reveal a prognostic signature of cancer-associated fibroblasts in head and neck squamous cell carcinoma

“…The predictability of the efficacy of the CAF risk score in immunotherapy was visualized using the receiver operating characteristic curve (ROC) curve. According to previous studies, CAFs are involved in the resistance of immune checkpoints inhibitors ( Bienkowska et al, 2021 ). As shown in Figure 7C , the integrated area under the curve (AUC) of the CAF signature, tumor mutation burden (TMB) and combined expression of CD8, CD274, and Merck18 was 0.776, which was higher than the AUC of TMB (AUC = 0.571) as well as the AUC of the expression of immune checkpoints (AUC = 0.760).…”

“…The diverse phenotypes and functions of CAFs indicate heterogeneity ( Richards et al, 2017 ; Li et al, 2018 ; Wen et al, 2019 ). In HNSCC, CAFs interact with cancer cells during the processes of tumor progression and invasion, metabolic reprogramming, angiogenesis, immunodepression, and tumor therapy ( Bienkowska et al, 2021 ). With the development of single-cell technology, single-cell RNA sequencing can be used to analyze the heterogenous cell population at a single cell resolution at the transcriptome level; this strategy was employed to study the heterogenous cells in the present study ( Ren et al, 2018 ).…”

Arecoline Is Associated With Inhibition of Cuproptosis and Proliferation of Cancer-Associated Fibroblasts in Oral Squamous Cell Carcinoma: A Potential Mechanism for Tumor Metastasis

“…CAFs have been regarded as the most prominent nonimmune tumor-promoting cells within cancers, especially in HNSCC (43). In summary, CAFs exert manifold pro-tumoral functions in oral cancers via immunosuppression, metabolic switch, tumor proliferation, angiogenesis, tumor invasion, and therapy resistance (44)(45)(46)(47)(48)(49).…”