CD4⁺ T cells expressing latency-associated peptide and Foxp3 are an activated subgroup of regulatory T cells enriched in patients with colorectal cancer

Jayashri Mahalingam; Chun-Yen Lin; Jy-Ming Chiang; Po-Jung Su; Yu-Yi Chu; Hsin-Yi Lai; Jian-He Fang; Ching-Tai Huang; Yung-Chang Lin

doi:10.1371/journal.pone.0108554

CD4⁺ T cells expressing latency-associated peptide and Foxp3 are an activated subgroup of regulatory T cells enriched in patients with colorectal cancer

PLoS One. 2014 Sep 30;9(9):e108554. doi: 10.1371/journal.pone.0108554. eCollection 2014.

Authors

Jayashri Mahalingam¹, Chun-Yen Lin¹, Jy-Ming Chiang², Po-Jung Su³, Yu-Yi Chu³, Hsin-Yi Lai⁴, Jian-He Fang⁵, Ching-Tai Huang⁶, Yung-Chang Lin⁷

Affiliations

¹ College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Gastroenterology-Hepatology, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
² College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Colorectal Surgery Section, Department of Surgery, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
³ Department of Hematology-Oncology, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
⁴ College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan.
⁵ Department of Gastroenterology-Hepatology, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
⁶ College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Infectious Diseases, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
⁷ College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Hematology-Oncology, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.

Abstract

Latency-associated peptide (LAP) - expressing regulatory T cells (Tregs) are important for immunological self-tolerance and immune homeostasis. In order to investigate the role of LAP in human CD4⁺Foxp3⁺ Tregs, we designed a cross-sectional study that involved 42 colorectal cancer (CRC) patients. The phenotypes, cytokine-release patterns, and suppressive ability of Tregs isolated from peripheral blood and tumor tissues were analyzed. We found that the population of LAP-positive CD4⁺Foxp3⁺ Tregs significantly increased in peripheral blood and cancer tissues of CRC patients as compared to that in the peripheral blood and tissues of healthy subjects. Both LAP⁺ and LAP⁻ Tregs had a similar effector/memory phenotype. However, LAP⁺ Tregs expressed more effector molecules, including tumor necrosis factor receptor II, granzyme B, perforin, Ki67, and CCR5, than their LAP⁻ negative counterparts. The in vitro immunosuppressive activity of LAP⁺ Tregs, exerted via a transforming growth factor-β-mediated mechanism, was more potent than that of LAP⁻ Tregs. Furthermore, the enrichment of LAP⁺ Treg population in peripheral blood mononuclear cells (PBMCs) of CRC patients correlated with cancer metastases. In conclusion, we found that LAP⁺ Foxp3⁺ CD4⁺ Treg cells represented an activated subgroup of Tregs having more potent regulatory activity in CRC patients. The increased frequency of LAP⁺ Tregs in PBMCs of CRC patients suggests their potential role in controlling immune response to cancer and presents LAP as a marker of tumor-specific Tregs in CRC patients.

Publication types

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

MeSH terms

Aged
Aged, 80 and over
Biomarkers, Tumor / genetics*
Biomarkers, Tumor / immunology
Case-Control Studies
Colorectal Neoplasms / diagnosis
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / immunology
Colorectal Neoplasms / pathology
Female
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / immunology
Gene Expression Regulation, Neoplastic*
Granzymes / genetics
Granzymes / immunology
Humans
Immune Tolerance
Immunologic Memory
Ki-67 Antigen / genetics
Ki-67 Antigen / immunology
Lymphatic Metastasis
Male
Middle Aged
Peptides / genetics*
Peptides / immunology
Perforin / genetics
Perforin / immunology
Protein Precursors / genetics*
Protein Precursors / immunology
Receptors, CCR5 / genetics
Receptors, CCR5 / immunology
Receptors, Tumor Necrosis Factor, Type II / genetics
Receptors, Tumor Necrosis Factor, Type II / immunology
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism*
T-Lymphocytes, Regulatory / pathology
Transforming Growth Factor beta / genetics*
Transforming Growth Factor beta / immunology

Substances

Biomarkers, Tumor
CCR5 protein, human
FOXP3 protein, human
Forkhead Transcription Factors
Ki-67 Antigen
Peptides
Protein Precursors
Receptors, CCR5
Receptors, Tumor Necrosis Factor, Type II
Transforming Growth Factor beta
latency-associated propeptide, TGF-beta
Perforin
GZMB protein, human
Granzymes

Grants and funding

This work was supported by the National Science Council, Taiwan (NSC Grant NSC 99-3112-B-182-011, 97-2314-B-182A-027) and CMRPG 380362, 380743, 392087 from Chang Gung Memorial Hospital. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.