Combination Chemotherapy Decreases Head and Neck Cancer Stem Cells

Objectives: Cisplatin induces stem cell self-renewal and increases the cancer stem cell (CSC) fraction in head and neck squamous cell carcinoma (HNSCC) models. The IL-6 pathway is enriched following cisplatin exposure, and high expression levels of serum IL-6 and tumor IL-6 receptor (IL-6R) are linked to poor patient survival. Our hypothesis is that therapeutic inhibition of the IL-6 pathway will suppress cisplatin-induced CSC self-renewal.
Methods: HNSCC cell lines were cultured and treated with cisplatin and/or IL-6R inhibitor (tocilizumab) in-vitro. Patient-derived xenograft (PDX) models implanted in SCID mice were treated with 0-5mg/kg cisplatin and/or 0-5mg/kg IL-6R inhibitor to assess therapeutic potential of combinatorial therapy. The resulting CSC proportion was analyzed by flow cytometry for ALDH activity and CD44 expression, whereas expression of key proteins in the IL-6 pathway and Bmi-1 were analyzed by western blot. Tumors were assessed for differences in growth rates and tumor volume.
Results: Combination therapy resulted in a decrease in IL-6 signaling and Bmi-1 expression in vitro. CSC proportion induced by cisplatin was reduced in the combination therapy group. These results were verified in parallel studies with the use of PDX-HNSCC tumor models. Combination therapy decreased tumor growth rate, fraction of CSC, and expression of Bmi-1 and IL-6 pathway proteins.
Conclusions: Collectively, these data suggest that IL-6 signaling plays an important role in cisplatin-related CSC changes and HNSCC tumor growth, as well as elucidate the mechanistic relationship between cisplatin and the IL-6 pathway. Our results suggest a novel treatment paradigm for HNSCC patients based on combination therapy with cisplatin and an inhibitor of the IL-6 pathway.