Expression of toll-like receptors in non-endemic nasopharyngeal carcinoma

Abstract

Background Nasopharyngeal carcinoma (NPC) is a malignant disease with an enigmatic etiology. NPC associates with Epstein-Barr virus (EBV) and human papillomaviruses (HPVs), while immunological factors also play a role in carcinogenesis. Toll-like receptors (TLRs) are pattern recognition receptors that participate in the immunological defence against pathogens, but their functions are also linked to cancer. Methods In our whole population-based study, we retrieved 150 Finnish NPC cases and studied their tumour samples for TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 expressions by immunohistochemistry, and for the presence of EBV and high-risk HPVs with EBV RNA and HPV E6/E7 mRNA in situ hybridizations. In addition, we analyzed the TLR expression patterns according to age, tumour histology, EBV/HPV status, and outcome. Results We found that all TLRs studied were highly expressed in NPC. Viral status of the tumours varied, and 62% of them were EBV-positive, 14% HPV-positive, and 24% virus-negative. The tumours with strong TLR2 nucl or TLR5 expression were mostly virus-negative or HPV-positive keratinizing squamous cell carcinomas, and the patients with these tumours were significantly older than those with mild or negative TLR2 nucl /TLR5 expression. In Kaplan-Meier analysis, the patients with strong TLR5 expression had worse survival compared to the patients with negative or mild TLR5 expression, but the results were linked to other patient and tumour characteristics. In multivariable-adjusted Cox regression analysis, the patients with positive TLR7 tumour expression had better overall survival than those with no TLR7 expression. The 5-year overall survival rates according to TLR7 expression were 66% (mild), 52% (moderate or strong), and 22% (negative). Conclusions TLRs are highly expressed in non-endemic NPC. Intensity of TLR2 and TLR5 expressions correlate with viral status, and TLR7 seems to be an independent prognostic factor of non-endemic NPC.

The Prognostic Value of Toll-Like Receptors in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis

“…These studies were published between 2013 and 2020, and they were conducted in Finland ( n = 6), China ( n = 5), Sweden ( n = 1), and Germany ( n = 1). The HNSCC histological subtypes included oropharyngeal squamous cell carcinoma (OPSCC) [ 10 , 11 ], oral squamous cell carcinoma (OSCC) [ 12 , 13 , 14 , 15 , 16 ], nasopharyngeal carcinoma (NPC) [ 17 ], base-of-tongue squamous cell carcinoma (BOTSCC) [ 18 ], and oral tongue squamous cell carcinoma (OTSCC) [ 19 , 20 , 21 ]. Long et al studied samples from tongue SCC (TSCC), however, it was not specified whether they were obtained from OTSCC or BOTSCC tissues [ 22 ].…”

“…The sample size per study ranged between 60 and 207 patients. The immunostaining in these studies was conducted on formalin-fixed paraffin-embedded samples, and targeted the following TLR subtypes: TLR-1 [ 17 , 22 ], TLR-2 [ 17 , 20 ], TLR-3 [ 12 ], TLR-4 [ 13 , 15 , 17 , 20 ], TLR-5 [ 10 , 11 , 16 , 17 , 18 , 20 , 21 ], TLR-7 [ 11 , 14 , 17 , 18 , 20 ], and TLR-9 [ 11 , 17 , 19 , 20 ]. The main characteristics of the included studies and the staining reagents are depicted in Table 1 and Table 2 , respectively.…”

“…For the quality assessment, five studies (38%) fulfilled all of the applied Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) criteria [ 10 , 11 , 17 , 19 , 21 ], while the eight remaining studies had one or more missing items of the applied REMARK checklist ( Supplementary Table S1 ). Results from the Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) critical appraisal tool revealed that all the included studies had no considerable reporting bias.…”

“…The expression of TLR-1 was significantly correlated with advanced tumour–node–metastasis (TNM) staging ( p < 0.05) in patients with TSCC [ 22 ]. In NPC, TLR-1 positivity was strong in 82% of the Finnish patient cohort, however, it had no correlation with the patients’ characteristics [ 17 ]. The expression of TLR-2 was also induced in 133/141 (94%) of the same cohort of NPC, and it was significantly correlated with older patient age ( p = 0.036) [ 17 ].…”

“…In NPC, TLR-1 positivity was strong in 82% of the Finnish patient cohort, however, it had no correlation with the patients’ characteristics [ 17 ]. The expression of TLR-2 was also induced in 133/141 (94%) of the same cohort of NPC, and it was significantly correlated with older patient age ( p = 0.036) [ 17 ]. In another Finnish cohort of 73 OTSCC patients, the higher expression of TLR-2 was correlated with deeper tumour invasion and grade ( p = 0.026; p = 0.021, respectively) [ 20 ].…”