The IL-6R and Bmi-1 axis controls self-renewal and chemoresistance of head and neck cancer stem cells

Alexandra E Herzog,Gregory T Wolf,Alexander T Pearson,Meera A Bhagat,Zhaocheng Zhang,Emily Bellile,Kristy A Warner,Peter J Polverini,Rogerio M Castilho,Jacques E Nör

doi:10.1038/s41419-021-04268-5

Abstract

Despite major progress in elucidating the pathobiology of head and neck squamous cell carcinoma (HNSCC), the high frequency of disease relapse correlates with unacceptably deficient patient survival. We previously showed that cancer stem-like cells (CSCs) drive tumorigenesis and progression of HNSCC. Although CSCs constitute only 2–5% of total tumor cells, CSCs contribute to tumor progression by virtue of their high tumorigenic potential and their resistance to chemo-, radio-, and immunotherapy. Not only are CSCs resistant to therapy, but cytotoxic agents actually enhance cancer stemness by activating transcription of pluripotency factors and by inducing expression of Bmi-1, a master regulator of stem cell self-renewal. We hypothesized therapeutic inhibition of interleukin-6 receptor (IL-6R) suppresses Bmi-1 to overcome intrinsic chemoresistance of CSCs. We observed that high Bmi-1 expression correlates with decreased (p = 0.04) recurrence-free survival time in HNSCC patients (n = 216). Blockade of IL-6R by lentiviral knockdown or pharmacologic inhibition with a humanized monoclonal antibody (Tocilizumab) is sufficient to inhibit Bmi-1 expression, secondary sphere formation, and to decrease the CSC fraction even in Cisplatin-resistant HNSCC cells. IL-6R inhibition with Tocilizumab abrogates Cisplatin-mediated increase in CSC fraction and induction of Bmi-1 in patient-derived xenograft (PDX) models of HNSCC. Notably, Tocilizumab inhibits Bmi-1 and suppresses growth of xenograft tumors generated with Cisplatin-resistant HNSCC cells. Altogether, these studies demonstrate that therapeutic blockade of IL-6R suppresses Bmi-1 function and inhibits cancer stemness. These results suggest therapeutic inhibition of IL-6R might be a viable strategy to overcome the CSC-mediated chemoresistance typically observed in HNSCC patients.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common solid tumor experiencing around 55,000 newly diagnosed cases every year in the United States [1]
This is true in human papillomavirus (HPV)-negative HNSCC patients, as HPV-negative disease exhibits worse prognosis and higher recurrence rates when compared to HPV-positive disease [5]
The molecular crosstalk within the tumor microenvironment has Lastly, to determine the effect of interleukin-6 receptor (IL-6R) silencing on the cancer stem-like cells (CSCs) fraction directly, flow cytometry analysis showed a decrease in ALDHhighCD44high cells in these cells when compared to vector controls (Fig. 1G and Supplementary Fig. S1)

Summary

INTRODUCTION

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common solid tumor experiencing around 55,000 newly diagnosed cases every year in the United States [1]. The molecular crosstalk within the tumor microenvironment has Lastly, to determine the effect of IL-6R silencing on the CSC fraction directly, flow cytometry analysis showed a decrease in ALDHhighCD44high cells in these cells when compared to vector controls (Fig. 1G and Supplementary Fig. S1). These data underline the significance of IL-6R signaling in maintaining been shown to assume a crucial part in maintaining the CSC pool and the stemness phenotype and self-renewal of head and neck CSCs. mediating HNSCC resistance to conventional chemotherapy [22, 23].

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS