In HPV-negative oropharyngeal squamous cell carcinoma, elevated toll-like receptor 2 immunoexpression may increase the risk of disease-specific mortality

Anna Kaisa Kylmä; Lauri Jouhi; Hesham Mohamed; Reija Randén-Brady; Antti Mäkitie; Timo Atula; Caj Haglund; Timo Sorsa; Jaana Hagström

doi:10.1016/j.oraloncology.2020.104778

In HPV-negative oropharyngeal squamous cell carcinoma, elevated toll-like receptor 2 immunoexpression may increase the risk of disease-specific mortality

Oral Oncol. 2020 Aug:107:104778. doi: 10.1016/j.oraloncology.2020.104778. Epub 2020 May 11.

Authors

Anna Kaisa Kylmä¹, Lauri Jouhi², Hesham Mohamed³, Reija Randén-Brady³, Antti Mäkitie⁴, Timo Atula², Caj Haglund⁵, Timo Sorsa⁶, Jaana Hagström⁷

Affiliations

¹ Department of Pathology, University of Helsinki, HUSLAB and Helsinki University Hospital, P.O. Box 21, 00014 Helsinki, Finland. Electronic address: anna.kylma@helsinki.fi.
² Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 263, 00029 HUS Helsinki, Finland.
³ Department of Pathology, University of Helsinki, HUSLAB and Helsinki University Hospital, P.O. Box 21, 00014 Helsinki, Finland.
⁴ Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 263, 00029 HUS Helsinki, Finland; Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden; Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁵ Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 20, 00014 Helsinki, Finland; Research Programs Unit, Translational Cancer Medicine, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland.
⁶ Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Central Hospital, P.O. Box 41, 00014 Helsinki, Finland; Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
⁷ Department of Pathology, University of Helsinki, HUSLAB and Helsinki University Hospital, P.O. Box 21, 00014 Helsinki, Finland; Research Programs Unit, Translational Cancer Medicine, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland; Department of Oral Pathology and Radiology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland.

PMID: 32403078
DOI: 10.1016/j.oraloncology.2020.104778

Abstract

Objectives: In oropharyngeal squamous cell carcinoma (OPSCC), toll-like receptors (TLR) 5 and 7 associate with the tumor's human papilloma virus (HPV) status (Jouhi et al., 2017). TLR 2, on the other hand, has been linked to head and neck squamous cell carcinoma (HNSCC), and to oral carcinogenesis (Farnebo et al., 2015; Binder Gallimidi et al., 2015). Here we investigated the presence of TLR 2 and 4 in HPV-positive and HPV-negative OPSCC, and their relationship to opportunistic oral pathogen Treponema denticola chymotrypsin-like protease (Td-CTLP) immunoexpression, clinical parameters, and patient outcome.

Materials and methods: Clinicopathological data of 198 unselected consecutive OPSCC patients came from hospital registries. Immunoexpression of TLRs 2 and 4 we evaluated by immunohistochemistry, and earlier in this patient series we studied immunoexpression of Td-CTLP and HPV DNA, HPV mRNA, and p16 status.

Results: Immunoexpression of both TLRs 2 and 4 showed a significant association with HPV-status. Strong expression was associated with HPV-positivity and mild expression with HPV-negativity. Patients with strong TLR 2 immunoexpression in the HPV negative subgroup had significantly poorer 5-year DSS (58%) than did patients with mild TLR 2 expression (77%), and strong TLR 2 immunoexpression remained as an independent factor linked to increased disease mortality in the multivariable setting (P = 0.019). No association existed between TLR 2 or 4 and Td-CTLP expression.

Conclusion: Our results support the role of TLR 2 receptor as a possible target for development of therapeutics as earlier proposed (Farnebo et al., 2015). The involvement of Td and other oral pathogens in carcinogenesis of OPSCC, remains open and calls for further study.

Keywords: Chymotrypsin-like protease; Dentilisin; Human papillomavirus; Oropharyngeal squamous cell carcinoma; Toll-like receptor; Treponema denticola.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Squamous Cell / immunology
Carcinoma, Squamous Cell / mortality*
Female
Humans
Male
Oropharyngeal Neoplasms / immunology
Oropharyngeal Neoplasms / mortality*
Toll-Like Receptor 2 / immunology*

Substances

Toll-Like Receptor 2