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The IL‐1/IL‐1R axis induces greater fibroblast‐derived chemokine release in human papillomavirus‐negative compared to positive oropharyngeal cancer
Author(s) -
AlSahaf Sarmad,
Hunter Keith D.,
Bolt Robert,
Ottewell Penelope D.,
Murdoch Craig
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31852
Subject(s) - chemokine , stromal cell , cancer research , cell culture , biology , interleukin 8 , immunology , cytokine , secretion , ccl5 , medicine , t cell , inflammation , immune system , endocrinology , genetics , il 2 receptor
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.