Long Non-Coding RNA HOXA Transcript Antisense RNA Myeloid-Specific 1-HOXA1 Axis Downregulates the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells in Lung Cancer.

Xinyu Tian,Lingxiang Mao,Yue Zhang,Shengjun Wang,Ting Wang,Jie Tian,Jie Ma,Huaxi Xu

doi:10.3389/fimmu.2018.00473

Abstract

HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA that has been shown to be a key regulator of myeloid cell development by targeting HOXA1. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that possess immunosuppressive function. However, the impact of HOTAIRM1 on the development of MDSCs remains unknown. In this study, we demonstrated that HOTAIRM1 was expressed in MDSCs and that overexpression of HOTAIRM1 could downregulate the expression of suppressive molecules in MDSCs. In addition, HOTAIRM1 levels were observed to be decreased in the peripheral blood cells of lung cancer patients compared with those of healthy controls. By analyzing HOTAIRM1 expression levels in different types of lung cancer, we found that HOTAIRM1 was mainly expressed in lung adenocarcinoma. Finally, it was confirmed that HOTAIRM1 could enhance the expression of HOXA1 in MDSCs and that high levels of HOXA1, the target gene of HOTAIRM1, could delay tumor progression and enhance the antitumor immune response by downregulating the immunosuppression of MDSCs. Taken together, this study illustrates that HOTAIRM1/HOXA1 downregulates the immunosuppressive function of MDSCs and may be a potential therapeutic target in lung cancer.

Highlights

Lung cancer has become the most commonly diagnosed cancer worldwide
We isolated CD11b+CD33+HLA-DR−CD14− Myeloid-derived suppressor cells (MDSCs) from tumor tissues of lung cancer patients, and qRT-PCR was used to detect the level of HOTAIRM1
We detected the HOTAIRM1 expression level in MDSCs induced from peripheral blood mononuclear cells (PBMCs) of healthy donors and found that the HOTAIRM1 expression level was decreased in the induced MDSCs compared with PBMCs without stimulation (Figure 1A)

Summary

Introduction

Lung cancer has become the most commonly diagnosed cancer worldwide. Lung cancer can be divided into non-small cell lung cancer, which includes adenocarcinoma (ADC) and squamous cell carcinoma, and small cell lung cancer. Antitumor therapy by targeting myeloid-derived suppressor cells (MDSCs), which are a main cause of tumor escape, is attracting increased interest [9]. Myeloid-derived suppressor cells are a population of heterogeneous cells derived from bone marrow Under physiological conditions, these immature myeloid cells can immediately differentiate into mature granulocytes, monocytes and macrophages. Under pathological conditions, especially cancer, MDSC differentiation is blocked, which leads to the expansion of MDSCs [10,11,12,13]. In both humans and mice, MDSCs can be divided into polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs) [14,15,16,17]. Therapies targeting MDSCs mainly involve promoting the differentiation of MDSCs, inhibiting the suppressive effect of MDSCs or eliminating MDSCs [19,20,21]

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