Abstract
Cancers of the oral cavity cause significant cancer-related death worldwide. While survival rates have improved in recent years, new methods of treatment are being investigated to limit disease progression and to improve outcomes, particularly in oral cavity squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMD). The emerging treatment modality of immunotherapy targets immune checkpoint molecules including PD-1 and its ligand PD-L1, CTLA-4, LAG-3, and TIM-3 to enhance the host immune response against tumours, and to limit the growth and progression of cancer cells. In this systematic review, we searched five databases for keywords pertaining to oral cancers and OPMDs, along with immune checkpoint inhibitors, in order to summarize the current status of their use and efficacy in these diseases. A total of 644 different articles were identified between 2004 and 2019, with 76 deemed suitable for inclusion in the study, providing a total of 8826 samples. Combined results show expression of PD-1 and PD-L1 in the majority of OPMD and OSCC samples, with expression correlating with increased progression and decreased survival rates. Immunotherapy agents pembrolizumab and nivolumab target PD-1 and have been shown to prolong survival rates and improve disease outcomes, especially in combination with chemotherapy or radiotherapy. Despite the equivocal nature of current evidence, there is support for the prognostic and predictive value of immune checkpoint molecules, especially PD-L1, and many studies provide support for the effective use of immune checkpoint inhibitors in the management of OSCC. Limited data is available for OPMD, therefore this should be the focus of future research.
Highlights
Cancer survival rates have improved significantly over the last few years [1]
PD-1 and its ligands were found to be expressed on infiltrating lymphocytes in oral lichen planus (OLP) which may have a role in tolerance induction in inflamed oral mucosa [51,71], this expression was lower than that expressed on CD8+ infiltrating lymphocytes in early stage tongue oral cavity squamous cell carcinoma (OSCC) [73]
Okada et al showed that the 5-year overall survival rates in low and high PD-L1 groups were 72.5% and 16.7%, respectively [18], and Ngamphaiboon et al showed that highly expressed PD-L1 (≥50%) was an independent prognostic factor for poor overall survival in anti-PD-1/PD-L1 untreated OSCC patients [36], further supporting PD-L1 as a prognostic biomarker of OSCC. These results indicate that expression of PD-L1, and possibly PD-1, are useful predictive biomarkers of disease response to immunotherapy and are potentially useful prognostic biomarkers for poor prognosis and disease progression and metastasis
Summary
Cancer survival rates have improved significantly over the last few years [1]. In the treatment of head and neck malignancies, including oral cavity squamous cell carcinoma (OSCC), immune checkpoint inhibitors constitute a significant breakthrough influencing treatment outcomes and improving overall survival [1]. Cancers 2020, 12, 1937 the ability of the immune system to detect and destroy cancer cells This is achieved by overcoming the mechanisms by which tumours evade and suppress the immune response, in essence, shifting the equilibrium back in favor of immune protection [5]. Regulatory T-cells play an important role in the tumour microenvironment (TME) They can mediate tolerance, suppress effector T-cells, and inhibit immune-mediated destruction. PD-L1 expression by tumour cells can lead to evasion of the immune response by inhibiting T-cell responses through conversion of TH1 CD4 T-cells to Tregs [6].
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