Human papillomavirus and other molecular markers in cancer of different oropharyngeal sub-sites

Background: Human papillomavirus (HPV) is a known risk factor for oropharyngeal cancer (OPSCC), and over the past few decades OPSCC has increased drastically due to an HPV epidemic. The oropharynx contains different sub-sites, where sub-sites rich in lymphoid tissue, such as the tonsils and the tongue base, are suggested to be more prone to harbor an HPV infection, and cancer of these sub-sites is more often HPV-positive (HPV+). Interestingly, patients with an HPV+ tonsillar or base of tongue cancer (TSCC or BOTSCC) generally have a better survival compared to patients with corresponding HPV-negative (HPV-) tumors. However, HPV does not have the same prognostic value in the other OPSCCs, and has been suggested to differ even depending on the histology of normal tissue surrounding TSCC. Moreover, we have previously shown that low levels of HLA class I (which presents antigens to the immune system) in HPV+ TSCC and BOTSCC was associated with a good prognosis, whereas the opposite was shown in HPV-tumors. Since current treatment often leads to severe side effects, de-escalation trials for patients with a predicted excellent prognosis would be an attractive alternative. Therefore, there is a need to understand the differences between OPSCC sub-sites, and find biomarkers that together with HPV status would identify patients that could benefit of de-escalated or targeted therapy.

Aims: To identify new prognostic markers in OPSCC and to study the importance of subdividing OPSCC. To study expression of proteins involved in antigen processing and presentation, in HPV+ and HPV-OPSCC, and how expression is affected by irradiation.

Results: In paper I and II, the expression of the antigen processing machinery (APM) components were evaluated both in the nucleus and in the cytoplasm. We showed that LMP10 and LMP7 had prognostic value in both HPV+ and HPV-TSCC and BOTSCC. We also found that APM components TAP2, LMP2, LMP7, and LMP10 were commonly suppressed in both HPV+ and HPV-TSCC and BOTSCC, and that LMP2 and LMP7 expression was correlated to HLA class I expression. In paper III, we found that radiotherapy had the ability to increase cell surface HLA class I expression in some HPV+ head and neck cancer cell lines, without an observed change at the transcriptional level. Our results from paper IV, show that HPV was significantly more prevalent in TSCC and BOTSCC as compared to the other oropharyngeal sub-sites. As described in paper V, the histology adjacent to TSCC varies and can be divided into TSCC, where normal tonsil-like adjacent tissue is present (specified TSCC (STSCC)), and absent (non-specified TSCC (NSTSCC)). We show that HPV is significantly more common in STSCC compared to NSTSCC. HPV+ STSCC patients have a better clinical outcome compared to HPV+ NSTSCC patients. However, no differences in clinical outcome was observed in patients with HPV-STSCC and NSTSCC.

Conclusions: This thesis provides increased understanding of differences between HPV+ and HPV-status in the context of OPSCC sub-sites. In addition, we have identified several prognostic biomarkers that together with HPV status and OPSCC sub-site, can contribute to improved personalized medicine for patients with OPSCC.

List of scientific papers

I. Tertipis N, Haeggblom L, Nordfors C, Grün N, Näsman A, Vlastos A, Dalianis T, and Ramqvist T. Correlation of LMP10 Expression and Clinical Outcome in Human Papillomavirus (HPV) Positive and HPV-Negative Tonsillar and Base of Tongue Cancer. PLoS One. 2014; 9(4): e95624.
https://doi.org/10.1371/journal.pone.0095624

II. Tertipis N, Haeggblom L, Grün N, Nordfors C, Näsman A, Dalianis T, and Ramqvist T. Reduced Expression of the Antigen Processing Machinery Components TAP2, LMP2, and LMP7 in Tonsillar and Base of Tongue Cancer and Implications for Clinical Outcome. Transl Oncol. 2015 Feb; 8(1): 10-17.
https://doi.org/10.1016/j.tranon.2014.11.002

III. Haeggblom L, Nordfors C, Tertipis N, Bersani C, Ramqvist T, Näsman A, Dalianis T. Effects of irradiation on human leukocyte antigen class I expression in human papillomavirus positive and negative base of tongue and mobile tongue squamous cell carcinoma cell lines. Int J Oncol. 2017 Mar 16.
https://doi.org/10.3892/ijo.2017.3916

IV. Haeggblom L, Ramqvist T, Tommasino M, Dalianis T, Näsman A. Time to change perspectives on HPV in oropharyngeal cancer. A systematic review of HPV prevalence per oropharyngeal sub-site the last 3 years. Papillomavirus Res. 2017 Dec;4:1-11.
https://doi.org/10.1016/j.pvr.2017.05.002

V. Haeggblom L, Attoff T, Hammarstedt-Nordenvall L, Näsman A. Human papillomavirus (HPV) and survival of patients per histological sub-site of tonsillar squamous cell carcinoma (TSCC). Cancer Medicine. 2018 Mar 23.
https://doi.org/10.1002/cam4.1400