In Vitro-Stimulated IL-6 Monocyte Secretion and In Vivo Peripheral Blood T Lymphocyte Activation Uniquely Predicted 15-Year Survival in Patients with Head and Neck Squamous Cell Carcinoma

Abstract

The study was performed in order to determine whether peripheral blood monocyte in vitro function, and lymphocyte in vivo activation at diagnosis, was associated with HPV tumor infection status and 15-year survival in head and neck squamous cell carcinoma (HNSCC) patients. Sixty-five patients from a consecutive cohort of newly diagnosed HNSCCs, together with 18 control patients, were included in the study. Monocyte responsiveness was assessed by measuring monocyte in vitro interleukin (IL)-6 secretions after 24 hours of LPS stimulation in cultures with a serum-free medium. T lymphocyte activation was determined as the fraction of CD71-positive cells on CD3-positive cells by flow cytometry, whereas HPV infection was determined by PCR on formalin-fixed paraffin-embedded (FFPE) tumor tissue. Disease-specific survivals and overall survivals were determined 15 years following inclusion. HPV-positive HNSCC patients had a lower monocyte LPS-stimulated IL-6 response. A high LPS-stimulated monocyte IL-6 response predicted a decreased survival rate (P=0.019). A high percentage of CD71-positive T lymphocytes also predicted an impaired prognosis (P=0.021). The predictive power of IL-6 monocyte LPS-stimulated responses was retained when adjusted for age, gender and TNM stage of the patients. The monocyte and T lymphocyte survival predictions were independent of each other. The survival was particularly low with a combined high activated monocyte and T lymphocyte status. In a multivariate analysis, IL-6 secretion and the percentage of CD71-positive T lymphocytes both uniquely predicted survival independent of HPV infection status. It is postulated that the natural and adaptive immune systems are separately and additionally linked to the clinical aggressiveness of HNSCCs.

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

“…The IL‐6 monocyte secretory levels were scored following the relative difference between the LPS pathogen‐associated molecular pattern (PAMP) and spheroid‐associated response, which consisted of several possible stimuli such as damage‐associated molecular pattern (DAMP) and secretory products of the spheroid cells . The current study cannot specifically answer this question, but do support a role of MNPs in the cancer trajectory.…”

“…We have previously shown that HPV+ compared to HPV‐ HNSCC patients had lower in vitro monocyte lipopolysaccharide (LPS)‐stimulated interleukin (IL)‐6 responses. A high LPS‐stimulated in vitro monocyte IL‐6 response furthermore predicted decreased survival, to some extent independent of HPV infection status . A high percentage of CD71‐positive T lymphocytes also predicted an impaired prognosis.…”

“…Several authors have shown that the functional status of the immune system is related to the prognosis of HNSCC . Furthermore, the immune system participates in the eradication of HPV‐positive (+) tumour cells during radiotherapy and also presumably so among HPV‐negative (−) patients.…”

“…IL‐6 levels are associated with a prognosis in various cancer diseases , HNSCC included . In general, several cytokines shown to be of prognostic value are abundantly secreted by activated MNPs .…”

MicroRNA‑146a regulates the transformation from liver fibrosis to cirrhosis in patients with hepatitis B via interleukin‑6

“…In the present study, the expression of IL-6 mRNA and protein in liver tissues, PBMCs and serum from patients with liver cirrhosis was higher than in patients with liver fibrosis, suggesting that inflammation may be aggravated during the transformation from liver fibrosis to cirrhosis. Upregulation of IL-6 may be caused by the activation of monocytes and lymphocytes, which can secrete abundant IL-6 factors and produce antigen immune responses (32).…”