Abstract

Human papillomavirus (HPV) is now recognised as a major aetiological agent in the pathogenesis of oropharyngeal carcinoma (OPC). HPV‐positive tumours are associated with better outcomes compared to HPV‐negative tumours, possibly due to differences in their aetiology and/or the tumour microenvironment. Increased numbers of tumour‐associated leukocytes have been observed in many cancers including OPC, with variable influence on prognosis depending on the leukocyte subpopulation investigated. Whether HPV status influences leukocyte recruitment to OPC remains unknown. This in‐vitro study examined differences in the chemoattractant capacity of HPV‐positive and HPV‐negative OPC cell lines. Gene and protein expression analysis demonstrated that whilst both monocultures of HPV‐positive and HPV‐negative cell lines, along with normal tonsillar fibroblasts (NTF), expressed low chemokine levels, NTF cultured with conditioned medium from HPV‐negative OPC cells expressed significantly higher levels of all chemokines tested compared to NTF incubated with the medium from HPV‐positive OPC cell lines. HPV‐negative OPC lines expressed IL‐1β mRNA whereas HPV‐positive cells did not, and NTF constitutively expressed IL‐1R1. Pre‐treatment with the IL‐R antagonist, anakinra or siRNA to IL‐1R1 significantly reduced chemokine secretion from NTF stimulated with conditioned medium from HPV‐negative tumour cells or recombinant IL‐1β (p < 0.05). These data suggest that secretion of chemokines is driven by the interaction between HPV‐negative OPC cells and stromal fibroblasts through an IL‐1/IL‐1R‐mediated mechanism that is less prominent within the HPV‐positive tumour microenvironment. These observations may explain differences in leukocyte sub‐populations recruited to HPV‐positive versus negative OPC and indicate that HPV status is a key determinant in controlling the inflammatory tumour microenvironment.

Highlights

  • Head and neck cancers (HNC) are the sixth most common cancer globally and ninth most common malignancy in males in the United States.[1]

  • The reasons for these differences remain largely unknown, it is generally accepted that the favorable prognosis of human papillomavirus (HPV)-positive oropharyngeal carcinoma (OPC) is related to the progressive genetic aberrations acquired in HPV-negative cancers, including key cell cycle regulators such as TP53 and RB1, whereas HPV-positive tumours arise from the effects of viral oncoproteins E6 and E7, which allow tumour cells to retain a wild-type TP53 and RB1 status.[12]

  • Data relating to the nature of leukocyte-recruiting chemokines released from HPV-positive and HPVnegative OPC is lacking

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Summary

Introduction

Head and neck cancers (HNC) are the sixth most common cancer globally and ninth most common malignancy in males in the United States.[1]. Given the complex cellular interactions that drive tumourigenesis; it is likely that disruption of other pathways are important in promoting the development of HPV-positive and -negative OPC

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