Finkel Kelsey A, Warner Kristy A, Kerk Samuel, Bradford Carol R, McLean Scott A, Prince Mark E, Zhong Haihong, Hurt Elaine M, Hollingsworth Robert E, Wicha Max S, Tice David A, Nör Jacques E
*Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
Neoplasia. 2016 May;18(5):273-281. doi: 10.1016/j.neo.2016.03.004. Epub 2016 Apr 15.
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(high)CD44(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(high)CD44(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.
头颈部鳞状细胞癌（HNSCC）中存在一小群具有独特致瘤性的癌症干细胞（CSC），这些细胞具有自我更新和多能性。我们最近发现，白细胞介素6（IL-6）可提高头颈部癌症干细胞（即醛脱氢酶高表达（ALDH(high)）、CD44高表达（CD44(high)）细胞）的存活率和致瘤潜力。在此，我们使用三种低传代患者来源的异种移植（PDX）头颈部鳞状细胞癌模型，对新型人源化抗IL-6抗体（MEDI5117）治疗性抑制IL-6的效果进行了表征。我们观察到，单药MEDI5117可抑制PDX-SCC-M1肿瘤的生长（P < 0.05）。该PDX模型源自先前未经治疗的头颈部鳞状细胞癌。相比之下，MEDI5117对代表耐药疾病的PDX模型（PDX-SCC-M0、PDX-SCC-M11）的总体肿瘤体积减小无效。与免疫球蛋白G（IgG）处理的对照组相比，低剂量MEDI5117（3毫克/千克）持续降低头颈部鳞状细胞癌PDX模型中癌症干细胞的比例，具体如下：PDX-SCC-M0（P < 0.001）、PDX-SCC-M1（P < 0.001）、PDX-SCC-M11（P = 0.04）。有趣的是，高剂量MEDI5117（30毫克/千克）可降低PDX-SCC-M11模型中的癌症干细胞比例（P = 0.002），但对PDX-SCC-M0和PDX-SCC-M1模型无效。MEDI5117介导超低附着板中培养的ALDH(high)CD44(high)细胞形成的球状体数量呈剂量依赖性减少（P < 0.05），支持其对头颈部癌症干细胞具有抑制作用。值得注意的是，单药MEDI5117降低了源自人HNSCC局部复发的PDX-SCC-M0的总体复发率。总体而言，这些数据表明，低剂量MEDI5117治疗性抑制IL-6可降低癌症干细胞比例，且辅助使用MEDI5117可抑制头颈部鳞状细胞癌临床前模型中的复发。
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