Abstract
Mucoepidermoid carcinoma (MEC) is the most frequent malignant salivary gland cancer. Response to chemoradiotherapy is modest, and therefore radical surgery remains the standard-of-care. Emerging evidence suggests that Interleukin (IL)-6 signaling correlates with the survival of cancer stem cells and resistance to therapy. Here, we investigated whether inhibition of IL-6 receptor (IL-6R) signaling with tocilizumab (humanized anti-human IL-6R antibody) sensitizes MEC to chemotherapy using human mucoepidermoid carcinoma cell lines (UM-HMC) and correspondent xenograft models. In vitro, we observed that tocilizumab inhibited STAT3 phosphorylation but had no measurable effect in MEC cell viability (UM-HMC-1,-3A,-3B). In contrast, the anti-tumor effect of single agent tocilizumab on MEC xenografts was comparable to paclitaxel or cisplatin. Combination of tocilizumab with cisplatin or paclitaxel enhanced the inhibitory effect of chemotherapy on xenograft growth (P < 0.05), time to failure (P < 0.01), decreased vascular endothelial growth factor (VEGF) expression and tumor microvessel density (P < 0.05) without added systemic toxicities. Notably, tocilizumab decreased the fraction of MEC cancer stem cells (ALDH(high)CD44(high)) in vitro, and prevented paclitaxel-induced increase in the fraction of cancer stem cells in vivo (P < 0.05). Collectively, these findings demonstrate that tocilizumab enhances the anti-tumor effect of conventional chemotherapy in preclinical models of mucoepidermoid carcinoma, and suggest that patients might benefit from combination therapy with an inhibitor of IL-6R signaling and chemotherapeutic agent such as paclitaxel.
Highlights
Salivary gland cancers are complex and diverse malignancies comprised of 24 morphologically different neoplasms [1,2,3,4]
To begin to understand the therapeutic potential of targeting IL-6 signaling in mucoepidermoid carcinomas, we evaluated the expression of key components of the IL-6 pathway in primary human tumors and in our xenograft models (Supplementary Figure S1)
Both human and xenograft tumors showed largely similar patterns of expression of these molecules (Supplementary Figure S1C). These descriptive results suggested that IL-6 could potentially play a significant role in the pathobiology of mucoepidermoid carcinoma, and encouraged us to perform developmental therapeutic studies with tocilizumab, a humanized anti-IL-6 receptor (IL-6R) antibody that has been approved by the FDA for treatment of rheumatoid arthritis since 2010
Summary
Salivary gland cancers are complex and diverse malignancies comprised of 24 morphologically different neoplasms [1,2,3,4]. Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland cancer, histologically characterized as a glandular epithelial neoplasm containing mucous, intermediate, and epidermoid cells [4,5,6]. Mucoepidermoid carcinomas are characterized by relentless growth and resistance to systemic therapy and radiotherapy. The most effective therapy remains radical surgery, which is typically accompanied by severe facial disfigurement, loss of function, and major consequences to the quality of life of patients [5, 1216]. The development of a mechanism-based therapeutic strategy that sensitizes these tumors to chemotherapy can potentially enhance the survival and quality of life of patients with mucoepidermoid carcinoma
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