CD47 Blockade Inhibits Tumor Progression through Promoting Phagocytosis of Tumor Cells by M2 Polarized Macrophages in Endometrial Cancer.

Shenglan Gu,Yao Liu,Qiong Fan,Xiao Sun,Yudong Wang,Ting Ni,Jing Wang,Ting Huang,Yiwei Chu,Yiwei Wang

doi:10.1155/2018/6156757

Shenglan Gu, Yao Liu + Show 8 more

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https://doi.org/10.1155/2018/6156757

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Abstract

There are rapidly emerging efforts to explore tumor-associated macrophages (TAMs) as a tumor therapy target. Tumor cells express CD47, which can interact with the macrophages' SIRPα transmitting a “don't eat me” signal to macrophages. The expression of CD47 increases in various tumors to evade immune attack. However, the expression of CD47 in endometrial cancer (EC) and the role of CD47-SIRPα in the TAMs which mediate the progression of EC remain unclear. Our study shows that there are increased TAMs in EC which dominantly consist of M2 macrophages and contribute to the progression of EC. We confirm that CD47 is highly expressed in EC tissue using the TCGA database, qPCR, and flow cytometry. Instead of directly promoting the apoptosis of EC cells, anti-CD47 blocking antibody promoted phagocytosis of EC cells by macrophages and the increased phagocytosis ability was mediated by M2 macrophages in a coculture assay. Besides, CD47 blockade inhibited the growth of the EC tumors in vivo and increased the infiltration of macrophages with antitumor ability in the tumor microenvironment (TME). These findings might assist in developing promising strategies that blocked the CD47-SIRPa interaction for EC therapy.

Highlights

Endometrial cancer is one of the most common gynecological malignancies, with 61,380 estimated new cases and 10,920 estimated deaths in 2017 in America [1]
M2 tumor-associated macrophages (TAMs) Are Closely Associated with the Tumor Progression in endometrial cancer (EC)
To study the distribution of macrophages, immunohistochemistry was used to evaluate the infiltration of TAMs in normal endometrium, endometrial atypical hyperplasia (EAH), and EC (Figure 1(a))

Summary

Introduction

Endometrial cancer is one of the most common gynecological malignancies, with 61,380 estimated new cases and 10,920 estimated deaths in 2017 in America [1]. Tumor immunotherapies which target the tumor microenvironment to increase the antitumor activity of the immune system elicit durable responses in many kind of tumors [3, 4]. Neoplastic cells can exploit a large variety of immune evasion mechanisms, including alterations in the expression of some molecules that inhibit antitumor immune response, such as programmed cell death 1 ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase (IDO) [7, 8]. Accumulating evidence indicates that anti-PD-1/PD-L immune checkpoint therapy may be effective in DNA polymerase epsilon- (POLE-) mutated and microsatellite instability (MSI) EC patients [9,10,11]. Considering that POLE-mutated and MSI EC patients account for a small

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