Stimulated monocyte IL-6 secretion predicts survival of patients with head and neck squamous cell carcinoma

Heimdal, John‐Helge; Kross, Kenneth W.; Klementsen, Beate; Olofsson, Jan; Aarstad, Hans Jørgen

doi:10.1186/1471-2407-8-34

Cited by 14 publications

(16 citation statements)

References 37 publications

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“…Interleukin-6 (IL-6) is a pleotropic cytokine with a wide range of biological activities and is well known for its role in inflammation, tumor progression and chemoresistance in HNSCC (28–33). Increases in IL-6 expression correlate with poor prognosis in HNSCC patients and patients resistant to chemotherapy have shown significantly higher serum IL-6 levels than those who did respond (28, 29, 31). …”

Section: Discussionmentioning

confidence: 99%

EGFR Inhibition Induces Proinflammatory Cytokines via NOX4 in HNSCC

Fletcher

Love-Homan

Sobhakumari

et al. 2013

Molecular Cancer Research

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Chronic inflammation plays a significant role in tumor promotion, migration and invasion. Using microarray analysis, we observed a profound increase in genes involved in pro-inflammatory pathways in epidermal growth factor receptor inhibitor (EGFRI)-treated head and neck squamous cell carcinoma (HNSCC) cell lines compared to their respective vehicle-treated cell lines. We hypothesized that the efficacy of EGFRIs may be offset by the pro-inflammatory response that these drugs produce in HNSCC tumor cells. We found that clinical EGFRIs such as erlotinib, cetuximab, lapatinib and panitumumab induced the secretion of pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-8, GM-CSF, TNFα and IFNγ. Focusing on IL-6, we found that erlotinib induced a time-dependent increase in IL-6 mRNA and protein expression and exogenous IL-6 was able to protect HNSCC cells from erlotinib-induced cytotoxicity. Conversely, an IL-6 receptor antagonist tocilizumab, sensitized HNSCC cells to erlotinib in vitro and in vivo. Inhibitors of NFκB, p38 and JNK suppressed erlotinib-induced IL-6 expression, suggesting an important role of NFκB and MAPK pathways in IL-6 expression. Furthermore, knockdown of NADPH oxidase 4 (NOX4) suppressed erlotinib-induced pro-inflammatory cytokines expression. Taken together, these results suggest that clinical EGFRIs induce the expression of pro-inflammatory cytokines via NOX4. Therefore, the anti-tumor activity of EGFRIs may be partially reduced by activation of NOX4-mediated pro-inflammatory pathways in HNSCC.

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Section: Discussionmentioning

confidence: 99%

EGFR Inhibition Induces Proinflammatory Cytokines via NOX4 in HNSCC

Fletcher

Love-Homan

Sobhakumari

et al. 2013

Molecular Cancer Research

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“…Serum IL-6 levels may predict survival in cancer patients [16], including both lung cancer [17] and HNSCC [18] patients. In accordance with this, we have shown that a high IL-6 secretion measured from lipopolysaccharide (LPS)-stimulated PB monocytes from HNSCC patients predicted an impaired intermediate-term prognosis [19]. It therefore seems that increased IL-6 levels are a negative prognostic factor in HNSCC patients, although to what extent this is affected by the HPV infection in the tumor is not known.…”

Section: Introductionmentioning

confidence: 89%

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

et al. 2015

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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.

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“…High serum levels of IL‐6 have been shown to herald impaired prognosis in HNSCC patients [15]. We have recently shown that a high level of IL‐6 secreted from MO isolated from HNSCC patients, stimulated with endotoxin (lipopolysaccharid, LPS) in vitro , is associated with decreased survival [16]. Secretion of MCP‐1 from MNP is of potential importance as this C‐C chemokine is associated with tumour‐associated macrophages (TAM) infiltration in HNSCC [17], which in turn has been associated with HNSCC prognosis [18].…”

Section: Introductionmentioning

confidence: 99%

Co‐culture of Head and Neck Squamous Cell Carcinoma Spheroids with Autologous Monocytes Predicts Prognosis

et al. 2008

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Co‐culture of monocytes with autologous fragment (F) spheroids originating from malignant (M) tumour or benign (B) control mucosa of head and neck squamous cell carcinoma (HNSCC) yields interleukin (IL)‐6 and monocyte chemo‐attractant protein (MCP)‐1 secretion. This study investigates the association between this cytokine co‐culture response and prognosis. Analysis of IL‐6 and MCP‐1 content of supernatants from monocytes in vitro co‐culture with autologous MF‐ or BF‐spheroids was investigated in a cohort of HNSCC patients (n = 65) diagnosed between 1998 and 2005, all of whom were treated with curative intent by primary surgery. The IL‐6 response was expressed as a fraction of the lipopolysaccharid response of the same batch of monocytes. Recurrence, survival and causes of death were then established following the second part of 2005. MCP‐1 levels did not predict prognosis. We found that increased levels of IL‐6 from autologous monocytes in co‐culture with MF‐spheroids predicted recurrence with a hazard ratio (HR) of 1.5 [confidence interval (CI): 1.01–2.60; P = 0.05] and co‐culture with BF‐spheroids and monocytes predicted recurrence (HR = 4.17; CI: 1.54–11.29; P = 0.005). The same results where obtained in addition with TNM stage of the patients. Simultaneous analysis of BF‐ and MF‐spheroid co‐culture IL‐6 responses as well as adjustment for age and TNM stage of the patients allowed prediction of total survival (HR = 3.1; CI: 1.11–8.56; P = 0.03) based on BF co‐culture levels. IL‐6 secreted upon in vitro co‐culture with monocytes and BF‐spheroids predicts recurrence and prognosis, whereas co‐culture with monocytes and MF‐spheroids predicts recurrence.

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Stimulated monocyte IL-6 secretion predicts survival of patients with head and neck squamous cell carcinoma

Cited by 14 publications

References 37 publications

EGFR Inhibition Induces Proinflammatory Cytokines via NOX4 in HNSCC

EGFR Inhibition Induces Proinflammatory Cytokines via NOX4 in HNSCC

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

Co‐culture of Head and Neck Squamous Cell Carcinoma Spheroids with Autologous Monocytes Predicts Prognosis

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