Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 21, 2017; 23(3): 455-463
Published online Jan 21, 2017. doi: 10.3748/wjg.v23.i3.455
Role of LAP+CD4+ T cells in the tumor microenvironment of colorectal cancer
Wu Zhong, Zhi-Yuan Jiang, Lei Zhang, Jia-Hao Huang, Shi-Jun Wang, Cun Liao, Bin Cai, Li-Sheng Chen, Sen Zhang, Yun Guo, Yun-Fei Cao, Feng Gao
Wu Zhong, Lei Zhang, Department of Gastrointestinal Surgery, Ganzhou Hospital of Nanchang University, Ganzhou 341000, Jiangxi Province, China
Zhi-Yuan Jiang, Department of Anorectal Surgery, Minzu Hospital of Guangxi Zhuang Autonomous Region, Nanning 530001, Guangxi Zhuang Autonomous Region, China
Jia-Hao Huang, Shi-Jun Wang, Cun Liao, Bin Cai, Li-Sheng Chen, Sen Zhang, Yun Guo, Yun-Fei Cao, Feng Gao, Department of Colorectal and Anal Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Author contributions: Zhong W, Jiang ZY and Zhang L contributed equally to this work; Chen LS, Zhang S and Cao YF, Gao F designed the research; Zhong W, Jiang ZY and Huang JH performed the research; Wang SJ, Liao C contributed new reagents/analytic tools; Cai B and Guo Y analyzed the data; Zhong W and Jiang ZY wrote the paper.
Supported by the National Natural Science Foundation of China, No. 81260316.
Institutional review board statement: This study was reviewed and approved by the First Affiliated Hospital of Guangxi Medical University Institutional Review Board, Nanning, China.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional unpublished data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Yun-Fei Cao, Professor, Department of Colorectal and Anal Surgery, First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. cyf0016@163.com
Telephone: +86-771-5356529 Fax: +86-771-5351442
Received: August 18, 2016
Peer-review started: August 22, 2016
First decision: October 10, 2016
Revised: November 9, 2016
Accepted: December 16, 2016
Article in press: December 19, 2016
Published online: January 21, 2017
Processing time: 148 Days and 21.1 Hours
Abstract
AIM

To investigate the abundance and potential functions of LAP+CD4+ T cells in colorectal cancer (CRC).

METHODS

Proportions of LAP+CD4+ T cells were examined in peripheral blood and tumor/paratumor tissues of CRC patients and healthy controls using flow cytometry. Expression of phenotypic markers such as forkhead box (Fox)p3, cytotoxic T-lymphocyte-associated protein (CTLA)-4, chemokine CC receptor (CCR)4 and CCR5 was measured using flow cytometry. LAP-CD4+ and LAP+CD4+ T cells were isolated using a magnetic cell-sorting system and cell purity was analyzed by flow cytometry. Real-time quantitative polymerase chain reaction was used to measure expression of cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β.

RESULTS

The proportion of LAP+CD4+ T cells was significantly higher in peripheral blood from patients (9.44% ± 3.18%) than healthy controls (1.49% ± 1.00%, P < 0.001). Among patients, the proportion of LAP+CD4+ T cells was significantly higher in tumor tissues (11.76% ± 3.74%) compared with paratumor tissues (3.87% ± 1.64%, P < 0.001). We also observed positive correlations between the proportion of LAP+CD4+ T cells and TNM stage (P < 0.001), distant metastasis (P < 0.001) and serum level of carcinoembryonic antigen (P < 0.05). Magnetic-activated cell sorting gave an overall enrichment of LAP+CD4+ T cells (95.02% ± 2.87%), which was similar for LAP-CD4+ T cells (94.75% ± 2.76%). In contrast to LAP-CD4+ T cells, LAP+CD4+ T cells showed lower Foxp3 expression but significantly higher levels of CTLA-4, CCR4 and CCR5 (P < 0.01). LAP+CD4+ T cells expressed significantly larger amounts of IL-10 and TGF-β but lower levels of IL-2, IL-4, IL-17 and interferon-γ, compared with LAP-CD4+ T cells.

CONCLUSION

LAP+CD4+ T cells accumulated in the tumor microenvironment of CRC patients and were involved in immune evasion mediated by IL-10 and TGF-β.

Keywords: LAP+CD4+ T cells; Colorectal cancer; Tumor microenvironment; Interleukin-10; Transforming growth factor-β

Core tip: Many carcinomas, including colorectal cancer, gastric and nasopharyngeal cancer, are associated with elevated numbers of T regulatory (Treg) cells. It is suggested that Treg cells promote tumor development and metastasis by inhibiting the proliferation of effector T lymphocytes. LAP+CD4+ T cells, a recently identified subset of CD4+ Treg cells, have 50-fold more potent immunosuppressive ability than traditional CD4+CD25+ T cells. Here, we present several lines of evidence correlating LAP+CD4+ T cells with colorectal cancer progression.