Title: 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 anti-tumor 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.