Targeting interleukin-6 trans-signaling in head and neck squamous cell carcinoma

Abstract

Inhibition of interleukin-6 trans-signaling by sgp130Fc is anti-tumorigenic in head and neck squamous cell carcinoma. Background: Head and neck squamous cell carcinoma (HNSCC) is a highly inflammatory cancer type, and interleukin-6 (IL-6) is associated with this phenotype. Elevated expression of IL-6 is linked to tumor progression, recurrence, metastasis, and resistance to therapy in HNSCC. However, targeting IL-6 or IL-6 receptor (IL-6R) has demonstrated little to no clinical efficacy. IL-6 signals through a classical signaling pathway via membrane IL-6R or a trans-signaling pathway via soluble IL-6R (sIL-6R). Recent evidence suggests that classical signaling induces acute, transient inflammation, eventually resulting in homeostasis; whereas trans-signaling may induce chronic, pro-tumorigenic inflammation. Therefore we propose that IL-6 trans-signaling is associated with the pro-inflammatory phenotype observed in HNSCC. We wanted to determine whether inhibition of IL-6 trans-signaling by sgp130Fc would better demonstrate anti-tumor efficacy and increase HNSCC tumor response to radiation, chemotherapy, and targeted therapy (cetuximab) compared to global IL-6 pathway inhibition. Method/Results: Baseline levels of IL-6, IL-6R, sIL-6R, and sgp130 proteins in HNSCC cells were determined using ELISA and flow cytometry. Cisplatin, radiation, and cetuximab treatments each induced HNSCC cell secretion of IL-6 and sIL-6R in vitro, yet adding sgp130Fc to those treatments did not further reduce clonogenic survival. Sgp130Fc treatment significantly suppressed SQ20B tumor growth in nude mice, whereas global IL-6 pathway inhibition by IL-6R antagonist tocilizumab did not; however, cetuximab reduced the efficacy of sgp130Fc in this animal model. Sgp130Fc also sensitized SQ20B xenograft tumors to radiation and chemotherapy in nude mice and suppressed SCCVII tumor growth in male but not female C3H/HeJ mice. Conclusion: Inhibition of IL-6 trans-signaling by sgp130Fc displayed significant antitumor effects as a single therapy and sensitized resistant HNSCC tumors to radiation and chemotherapy in vivo; however, sgp130Fc did not reduce survival of HNSCC cells in vitro. These results suggest that the efficacy of sgp130Fc relies on targeting another part of the microenvironment instead of tumor cells directly. Sgp130Fc has promise both as a single therapy and potentially as combined therapy with radiation and chemotherapy in HNSCC. Chapter 1: Introduction Section I: Head and neck squamous cell carcinoma (HNSCC) Etiology and statistics of HNC/HNSCC Head and neck cancer (HNC) originates from tissues in the oral cavity, nasal cavity, pharynx, larynx, or salivary glands, at least 90% of which is squamous cell carcinoma (HNSCC) [1]. More than 65,000 new incidences of HNC were estimated to occur in the United States in 2017 (Table 1) [2, 3]. Table 1. Overall HNC incidence and survival in United States [3].

Correlation Between Interleukin 6 with Nasopharyngeal Carcinoma in the Minangkabau Ethnic Group

“…Zergoun [16] in North Africa concluded that the plasma levels of IL-6 in healthy people were 15.51±5.14pg/ml. Dahl [10] in United States obtained an average plasma IL-6 level of 1.82±0.30pg/ml. This study did not explore the condition of control plasma respondents of the Minangkabau ethnic group, such as menstrual cycle and body weight status.…”

“…Increased blood level of IL-6 reflects IL-6 level in the tumor microenvironment and indicated the progression of disease. Dahl [10] explained that a STAT-3 played a role in oncogenic activity in tumors, such as mutations that would cause Janus Kinase/ Signal Transducer and Activator of Transcription-3 (JAK/STAT-3) signal activations. JAK/STAT-3 signaling mediated by IL-6 cause positive feedback of IL-6 synthesis that promote tumor growth, proliferation and metastasis.…”

“…Siltuximab and Tocilizumab are IL-6 signaling inhibitors that have been approved by Food and Drug Administration (FDA) in Castleman's disease and rheumatoid arthritis. In head and neck cancer, the use of Pembrolizumab and Nivolumab are targeted therapies that are currently in phase III clinical trial stage [9,10].…”