CD4+CCR8+ Tregs in ovarian cancer: a potential effector Tregs for immune regulation

Shuna Liu; Ziqi Tao; Jianfang Lou; Rong Li; Xin Fu; Juan Xu; Ting Wang; Lei Zhang; Wenwen Shang; Yepeng Mao; Fang Wang

doi:10.1186/s12967-023-04686-3

CD4⁺CCR8⁺ Tregs in ovarian cancer: a potential effector Tregs for immune regulation

J Transl Med. 2023 Nov 10;21(1):803. doi: 10.1186/s12967-023-04686-3.

Authors

Shuna Liu^#^{1

2}, Ziqi Tao^#^{1

2}, Jianfang Lou^#^{1

2}, Rong Li^{1

2

3}, Xin Fu^{1

2}, Juan Xu^{1

2

4}, Ting Wang^{1

2}, Lei Zhang^{1

2

5}, Wenwen Shang^{1

2}, Yepeng Mao^{1

2}, Fang Wang^{6

7}

Affiliations

¹ Department of Laboratory Medicine, The First Affiliated Hospital with Nanjing Medical University, No. 300 of Guangzhou Road, Nanjing, 210029, China.
² Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, 210029, China.
³ Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing, 210004, China.
⁴ Department of Laboratory Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225300, China.
⁵ Department of Gynecology, The Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian, 223300, China.
⁶ Department of Laboratory Medicine, The First Affiliated Hospital with Nanjing Medical University, No. 300 of Guangzhou Road, Nanjing, 210029, China. wangfang@njmu.edu.cn.
⁷ Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, 210029, China. wangfang@njmu.edu.cn.

^# Contributed equally.

Abstract

Background: Tregs are key drivers of immunosuppression in solid tumors. As an important chemokine receptor on Tregs, the regulatory effect of CCR8 on tumor immunity has received more and more attention. However, the current research on CCR8 in the immune microenvironment of ovarian cancer has not been clear.

Methods: Bioinformatics analysis was used to compare the transcriptome differences between CD4⁺ T cells in the peripheral circulation and infiltrated in ovarian tumor tissues. RT-PCR was used to detect the expression levels of chemokine receptor-related differential genes on CD4⁺ T cells in peripheral blood and ovarian tumor tissues. Multiparameter flow cytometry was used to detect the proportion and phenotypic characteristics of CD4⁺CCR8⁺ Tregs and CD4⁺CCR8^- Tregs in different sample types. The expression level of CCR8 ligands was detected at multiple levels. To explore the important role of CCR8-CCL1 and CCR8-CCL18 axis in the migration and invasion of CD4⁺CCR8⁺ Tregs into ovarian tumor tissues by establishing a chemotaxis system in vitro.

Results: In this study, significantly different gene expression profiles were found between peripheral circulating CD4⁺ T cells and infiltrating CD4⁺ T cells in ovarian tumor tissues, in which chemokine-chemokine receptor signaling pathway was significantly enriched in all three groups of differential genes. The expression level of CCR8 in infiltrating CD4⁺ T cells of ovarian cancer tissue was significantly higher than that in peripheral blood of healthy controls and ovarian cancer patients, and high expression of CCR8 was significantly correlated with advanced tumor stage and poor differentiation. CD4⁺CCR8⁺ Tregs are the main type of infiltrating CD4⁺ Tregs in ovarian tumor tissues, which have stronger immunosuppressive phenotypes, secrete more inhibitory cytokines and have stronger proliferation ability. The ligands CCL1 and CCL18 corresponding to CCR8 were significantly overexpressed in ovarian tumor tissues, and the CCR8-CCL1 and CCR8-CCL18 axis played a key role in the migration and infiltration of CD4⁺CCR8⁺ Tregs into ovarian tumor tissues.

Conclusions: The results of this study may help to understand the phenotypic characteristics and recruitment process of Tregs in the tumor, and provide new ideas for improving the immunosuppressive status of the ovarian cancer microenvironment.

Keywords: CCR8; Chemokine; Gene expression profile; Ovarian cancer; Regulatory T cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chemotaxis
Female
Humans
Immunosuppression Therapy
Ovarian Neoplasms* / genetics
Ovarian Neoplasms* / metabolism
Receptors, CCR8 / genetics
Receptors, CCR8 / metabolism
Receptors, Chemokine / metabolism
T-Lymphocytes
T-Lymphocytes, Regulatory
Tumor Microenvironment

Substances

Receptors, Chemokine
CCR8 protein, human
Receptors, CCR8