<p>Neutrophils infiltration and its correlation with human papillomavirus status in the oral squamous cell carcinoma</p>

Abstract

Purpose: One of the cardinal etiological factors for oral squamous cell carcinoma (OSCC) is Human papillomavirus (HPV). Neutrophils were potential targets of immune therapy for patients with OSCC. The objective of this study was to determine if neutrophils density and HPV status can be used to define a high-risk category of patients in OSCC and to investigate the possible relationship between them. Patients and methods: We performed immunohistochemistry to probe neutrophils infiltration and HPV (P16) expression in 81 patients with OSCC. Prognostic factors for cancer-related survival were evaluated by univariate and multivariate analyses. We used the detection of cytokines to investigate the possible molecular mechanisms between neutrophils infiltration and HPV status. Results: There were significantly higher numbers of CD15+ neutrophils infiltration in OSCC tissues. Higher numbers of CD15+ neutrophils infiltration was related to stage Ⅲ，Ⅳ ( p <0.001), poor grade ( p <0.001), lymph node metastasis ( p =0.014), and the higher preoperative neutrophil-lymphocyte ratio (NLR) ( p <0.001). HPV-negative status was also associated with stage Ⅲ，Ⅳ ( p= 0.001), poor grade ( p= 0.002), lymph node metastasis ( p =0.005), radiotherapy ( p =0.038), and the higher NLR ( p =0.002). The high density of neutrophils was associated with worse cancer-related survival time ( p <0.001) and was an independent prognostic factor for OSCC, while the HPV-positive group was associated with better cancer-related survival time. Moreover, high density of neutrophils was correlated with HPV-negative status in OSCC ( p <0.001). Detection of cytokines and chemokines revealed that one of the chemotactic factors of neutrophils, IL-8, was exhibited relatively low expression by HPV-positive OSCC cells, whereas HPV-negative OSCC cells were found to drive an IL-8 secretion profile. Conclusion: Neutrophils infiltration and HPV status appear to be prognostic parameters for OSCC. Overexpression of HPV18 E7 on OSCC cells may participate in depressing neutrophils infiltration to some extent through downregulating expression of IL-8.

Increased Abundance of Tumour-Associated Neutrophils in HPV-Negative Compared to HPV-Positive Oropharyngeal Squamous Cell Carcinoma Is Mediated by IL-1R Signalling

“…However, similar data have been reported for OSCC [24], although this form of cancer rarely harbours oncogenic HPV [25]. Here, Li et al, observed increased abundance of CD15+ neutrophils in HPV-negative compared to HPV-positive OSCC, as well as finding that high levels of neutrophils correlated with poor 5-year survival, increased lymph node metastasis and were an independent prognostic factor for OSCC [24]. Using The Cancer Genome Atlas (TCGA) data set Chen et al, also found a higher neutrophil genetic imprint for HPV-negative compared to HPV-positive head and neck cancer [26].…”

“…However, the chemokine profiles detected using these MCTS directly correlated with the profiles observed for other HPV-positive/negative cell lines in our previous 2D study [13], providing some evidence that these phenomena is not cell line specific but may be a general occurrence for HPV status. In support of this, analysis of the Gene Expression Omnibus (GEO) and TCGA databases showed significantly elevated levels of CXCL8 in HPV-negative compared to HPV-positive tumours [24], consistent with our in vitro 3D model data. In addition to CXCL8, increased abundance of other neutrophil-specific chemokines such as CXCL1, CXCL5 and CXCL6 is likely, as evidenced by our previous cytokine array analysis [13], and this may further skew the imbalance in leukocyte recruitment in favour of preferential neutrophil recruitment.…”

“…Unfortunately, we were unable to correlate TAN levels with prognosis for HPV status cases due to the sample size. However, similar data have been reported for OSCC [24], although this form of cancer rarely harbours oncogenic HPV [25]. Here, Li et al, observed increased abundance of CD15+ neutrophils in HPV-negative compared to HPV-positive OSCC, as well as finding that high levels of neutrophils correlated with poor 5-year survival, increased lymph node metastasis and were an independent prognostic factor for OSCC [24].…”

Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes

“…Experimental and epidemiological evidence indicate an association between chronic inflammation [39,40] and PMN infiltration [25] with cancer prognosis. In addition, high risk HPV infections are closely related with other malignancies, in particular oropharyngeal cancer, where inflammation and high PMN infiltration negatively correlate with patient survival [41,42]. Therefore, novel approaches aimed at modulating PMN actions to control HPV-cancers are of wide interest.…”

Oral Neutrophils: Underestimated Players in Oral Cancer

“…As interferons have been shown to have anti-tumoral capacity ( 114 ) and to prime anti-tumor phenotype of neutrophils ( 8 , 10 , 115 ), this phenomenon should be further exploited. Overexpression of HPV proteins in OSCC cells is also associated with an impaired neutrophil infiltration to the tumor, possibly due to the downregulated expression of IL-8 ( 116 ). While recently a comprehensive single cell RNA sequencing study investigated the differences between intratumoral immune cells isolated from HPV + and HPV – HNC [large differences between B-cells, myeloid cells and conventional CD4 + T-cells, rare differences between regulatory CD4 + T-cells and CD8 + T-cells] ( 117 ), there is to the best of our knowledge no study investigating the influence of HPV status on oPMN phenotype and function.…”