Anti-tumor effect of inhibition of IL-6 signaling in mucoepidermoid carcinoma.
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.
Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.|Department of Otolaryngology/Head Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Daiki
D
Mochizuki
Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
April
A
Adams
Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
Kristy A
KA
Warner
Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
Zhaocheng
Z
Zhang
Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.|Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
Alexander T
AT
Pearson
Department of Otolaryngology/Head Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Kiyoshi
K
Misawa
Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
Scott A
SA
McLean
Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
Gregory T
GT
Wolf
Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.|Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.|Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan, USA.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
Jacques E
JE
Nör
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018277:Carcinoma, Mucoepidermoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011897:Random Allocation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093242:Interleukin-6 Inhibitors
D061067:Antibodies, Monoclonal, Humanized; D002945:Cisplatin; D015850:Interleukin-6; D017239:Paclitaxel; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C494086:STAT3 protein, human; C502936:tocilizumab
IL-6R; salivary gland cancer; tocilizumab; tumor initiating cells; tumorigenesis