IL-6 Inhibition With MEDI5117 Decreases The Fraction of Head and Neck Cancer Stem Cells and Prevents Tumor Recurrence

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• 作者：Kelsey A. Finkel^* ; Kristy A. Warner^* ; Samuel Kerk^* ; Carol R. Bradford^&dagger ; ; ^# ; Scott A. McLean^&dagger ; ; ^# ; Mark E. Prince^&dagger ; ; ^# ; Haihong Zhong^&Dagger ; ; Elaine M. Hurt^&Dagger ; ; Robert E. Hollingsworth^&Dagger ; ; Max S. Wicha^§ ; ; ^# ; David A. Tice^&Dagger ; ; Jacques E. Nö ; r^* ; ^&dagger ; ; ^¶ ; ; ^# ; ^{jenor@umich.edu" class="auth_mail" title="E-mail the corresponding author}
• 刊名：Neoplasia
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：18
• 期：5
• 页码：273-281
• 全文大小：2148 K

文摘

Head and neck squamous cell carcinomas (HNSCC) exhibit a small population of uniquely tumorigenic cancer stem cells (CSC) endowed with self-renewal and multipotency. We have recently shown that IL-6 enhances the survival and tumorigenic potential of head and neck cancer stem cells (i.e. ALDH^highCD44^high cells). Here, we characterized the effect of therapeutic inhibition of IL-6 with a novel humanized anti-IL-6 antibody (MEDI5117) using three low-passage patient-derived xenograft (PDX) models of HNSCC. We observed that single agent MEDI5117 inhibited the growth of PDX-SCC-M1 tumors (P < .05). This PDX model was generated from a previously untreated HNSCC. In contrast, MEDI5117 was not effective at reducing overall tumor volume for PDX models representing resistant disease (PDX-SCC-M0, PDX-SCC-M11). Low dose MEDI5117 (3 mg/kg) consistently decreased the fraction of cancer stem cells in PDX models of HNSCC when compared to IgG-treated controls, as follows: PDX-SCC-M0 (P < .001), PDX-SCC-M1 (P < .001), PDX-SCC-M11 (P = .04). Interestingly, high dose MEDI5117 (30 mg/kg) decreased the CSC fraction in the PDX-SCC-M11 model (P = .002), but not in PDX-SCC-M0 and PDX-SCC-M1. MEDI5117 mediated a dose-dependent decrease in the number of orospheres generated by ALDH^highCD44^high cells cultured in ultra-low attachment plates (P < .05), supporting an inhibitory effect on head and neck cancer stem cells. Notably, single agent MEDI5117 reduced the overall recurrence rate of PDX-SCC-M0, a PDX generated from the local recurrence of human HNSCC. Collectively, these data demonstrate that therapeutic inhibition of IL-6 with low-dose MEDI5117 decreases the fraction of cancer stem cells, and that adjuvant MEDI5117 inhibits recurrence in preclinical models of HNSCC.