Targeting LSD1 suppresses stem cell-like properties and sensitizes head and neck squamous cell carcinoma to PD-1 blockade

Yong Han,Jiong Deng,Liu Liu,Xiangkai Zhang,Zhiyuan Zhang,Weimin Ye,Shengming Xu,Shuli Liu,Yang Wang

doi:10.1038/s41419-021-04297-0

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive tumor with poor clinical outcomes due to recurrence, metastasis, and treatment resistance. Cancer stem cells (CSCs), a small population among tumor cells, are proposed to be responsible for tumor initiation, progression, metastasis, drug resistance, and recurrence. Here we show that high LSD1 expression was a predictor of poor prognosis for HNSCC patients. We found that high expression of LSD1 is essential for the maintenance of the CSC properties by regulating Bmi-1 expression. Moreover, tumor LSD1 ablation suppresses CSC-like characteristics in vitro and inhibits tumorigenicity in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PDL1 levels, which compromises antitumor immunity and reduces antitumor efficacy in an immune-competent mouse model. Functionally, the combination of LSD1 inhibitor and anti-PD-1 monoclonal antibody can overcome tumor immune evasion and greatly inhibit tumor growth, which was associated with reduced Ki-67 level and augmented CD8+ T cell infiltration in immunocompetent tumor-bearing mouse models. In summary, these findings provide a novel and promising combined strategy for the treatment of HNSCC using a combination of LSD1 inhibition and PD-1 blockade.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a low 5-year survival rate and poor prognosis [1]
LSD1 is aberrantly expressed in HNSCC and associated with a poor prognosis To explore the role of LSD1 in HNSCC progression, we first mouse model
In this study, we provided a model (Fig. 8) showing that LSD1 was overexpressed in HNSCC cancer cells and conferred Cancer stem cells (CSCs)-like features mediated through Bmi-1 expression to them

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a low 5-year survival rate and poor prognosis [1]. Despite a variety of advances in combined modality treatments over the past three decades, the 5-year survival rate for HNSCC patients remains unsatisfactory, largely due to uncontrolled local recurrence and metastasis [2]. Cancer stem cells (CSCs), known as cancer-initiating cells, have been proposed to play vital roles in treatment resistance and metastasis [3]. Given their tumor-initiating capacity, surviving CSCs are qualified to serve as precursors of new tumor masses, leading to local recurrence [4].

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Results

Conclusion