Abstract
The incidence of human papillomavirus (HPV)-associated cancer is increasing and HPV is now implicated in the aetiology of more than 60% of all oropharyngeal squamous cell carcinomas (OPSCC). In OPSCC, innate immune cells such as neutrophils and macrophages generally correlate with poor prognosis, whilst adaptive immune cells, such as lymphocytes, tend to correlate with improved prognosis. This may, in part, be due to differences in the immune response within the tumour microenvironment leading to the recruitment of specific tumour-associated leukocyte sub-populations. In this study, we aimed to examine if differences exist in the levels of infiltrated leukocyte sub-populations, with particular emphasis on tumour-associated neutrophils (TAN), and to determine the mechanism of chemokine-induced leukocyte recruitment in HPV-positive compared to HPV-negative OPSCC. Immunohistochemical analysis showed that HPV-negative OPSCC contained significantly more neutrophils than HPV-positive tumours, whilst levels of CD68+ macrophages and CD3+ lymphocytes were similar. Using a 3D tissue culture model to represent tumour-stromal interactions, we demonstrated that HPV-negative tumour-stromal co-cultures expressed significantly higher levels of CXCL8, leading to increased neutrophil recruitment compared to their HPV-positive counterparts. HPV-negative OPSCC cells have previously been shown to express higher levels of IL-1 than their HPV-positive counterparts, indicating that this cytokine may be responsible for driving increased chemokine production in the HPV-negative 3D model. Inhibition of IL-1R in the tumour-stromal models using the receptor-specific antagonist, anakinra, dramatically reduced chemokine secretion and significantly impaired neutrophil and monocyte recruitment, suggesting that this tumour-stromal response is mediated by the IL-1/IL-1R axis. Here, we identify a mechanism by which HPV-negative OPSCC may recruit more TAN than HPV-positive OPSCC. Since TAN are associated with poor prognosis in OPSCC, our study identifies potential therapeutic targets aimed at redressing the chemokine imbalance to reduce innate immune cell infiltration with the aim of improving patient outcome.
Highlights
The worldwide increasing incidence of human papillomavirus (HPV)-driven oropharyngeal squamous cell cancer (OPSCC) has raised the profile of these tumours and intensified interest in this area of cancer research [1]
The tumour microenvironment plays a major role in directing the course of tumour progression, and factors that regulate the immune response and direct the infiltration of tumourassociated leukocytes are key to this process [21]
Our patient cohort was relatively small, HPV status still stratified the patient groups in terms of outcome, where patients with HPV-positive OPSCC displayed significantly improved 5-year survival than those with HPV-negative tumours, as observed in several other studies [2, 6, 22, 23]
Summary
The worldwide increasing incidence of human papillomavirus (HPV)-driven oropharyngeal squamous cell cancer (OPSCC) has raised the profile of these tumours and intensified interest in this area of cancer research [1]. Of particular interest is the finding that HPV-positive OPSCC generally display improved prognosis and response to therapy than their HPV-negative counterparts, whose aetiology is generally linked to DNA damage by classical risk factors such as tobacco use and alcohol consumption rather than viral infection [2]. There is good evidence to suggest that HPV-positive OPSCC contain abundant CD8+ T-cells that can recognise tumour cell-expressed HPV antigens, enabling activation of adaptive immune responses to eliminate cancer cells and impart improved outcome [5,6,7]. Increased levels of TAM and TAN correlate with poor prognosis in oral squamous cell carcinoma (OSCC) [8, 9], the levels of TAM in HPV-positive/negative OPSCC are less well-characterised and to date there are no published studies correlating abundance of TAN in OPSCC with HPV status
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