In vitro Monocyte IL‐6 Secretion Levels Following Stimulation with Autologous Spheroids Derived from Tumour or Benign Mucosa Predict Long‐term Survival in Head and Neck Squamous Cell Carcinoma Patients

Abstract

MCP-1/IL-6 in vitro monocyte secretion upon coculture with autologous fragment spheroids was studied in relation to patient 5- and 10-year overall survival rates in head and neck squamous cell carcinoma (HNSCC) patients (n = 65) diagnosed between 1998 and 2005, nine of whom had an human papilloma virus (HPV) tumour infection. The spheroids were harvested from malignant or benign tissue during primary surgery. Two weeks following surgery, freshly isolated autologous monocytes and benign or malignant spheroids were cocultured 24 h in vitro. The IL-6 secretion was expressed as a fraction of the lipopolysaccharide (LPS) response from the same batch of monocytes. HPV status was obtained by employing PCR analyses of primary diagnostic blocks. IL-6/MCP-1 response levels were not found to be dependent on HPV infection status. MCP-1 secretion did not predict prognosis, nor did in vitro IL-6 monocyte background or LPS-stimulated IL-6 secretion. At 5-year observation, dichotomized IL-6 levels following monocyte coculture, with both malignant and benign spheroids, showed a strong trend towards predicting survival, that is a low monocyte malignant coculture response showed a survival of 31 ± 17 versus 58 ± 17% with a high such response (P = 0.057). When studying monocyte IL-6 coculture responses evaluating benign and malignant spheroid results statistically together, a prediction of survival up to 10 years was found (hazard ratio = 0.48; confidence interval = 0.24-0.96; P < 0.05) with double low IL-6 responses. This survival prediction was also present after an adjustment for HPV tumour infection status. In conclusion, monocyte IL-6 in vitro secretion in cocultures with autologous spheroids/serum from HNSCCs predicted 5- and 10-year survivals, both with and without tumour HPV tumour adjustment.

Tumor Infiltration Levels of CD3, Foxp3 (+) Lymphocytes and CD68 Macrophages at Diagnosis Predict 5-Year Disease-Specific Survival in Patients with Oropharynx Squamous Cell Carcinoma

“…The same is the case with HNSCC [21] patients. We [22,23] and others [5] have also shown an association between monocyte tumor reactivity and prognosis. We have therefore aimed at studying the level of macrophage infiltration as measured by CD68-positive cell levels in patients with OPSCC tumors.…”

Tumor HPV Status, Level of Regulatory T Cells and Macrophage Infiltration Predict up to 20-Year Non-Disease-Specific Survival in Oropharynx Squamous Cell Carcinoma Patients

“…In a review paper, the IL-6 serum level at diagnosis was significantly correlated to survival in 82/101 series comprising 9917 out of 11,583 patients with 23 different cancer types [ 24 ], including HNSCC [ 25 ] patients. We [ 26 , 27 ] and others [ 6 ] have also shown an association between monocyte tumor reactivity and HNSCC prognosis. We therefore aimed to study the level of macrophages as measured by CD68-positive cell infiltration in the studied OPSCC tumors in relation to long-term prognosis.…”

Predictors of circulating INTERLEUKIN-6 levels in head and neck cancer patients

“…Activated monocytes/macrophages [ 59 – 61 ] and epithelial cells [ 62 ] have been described as producing pro-inflammatory cytokines, including IL-6. These cell types can be activated by carcinogens found in tobacco products [ 63 , 64 ].…”