title: CD4⁺ T cells expressing latency-associated peptide and Foxp3 are an activated subgroup of regulatory T cells enriched in patients with colorectal cancer.
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.
authors.affiliation: College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Gastroenterology-Hepatology, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
authors.forename: Jayashri
authors.initials: J
authors.lastname: Mahalingam
authors.affiliation: College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Gastroenterology-Hepatology, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Jy-Ming
authors.initials: JM
authors.lastname: Chiang
authors.affiliation: Department of Hematology-Oncology, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
authors.forename: Po-Jung
authors.initials: PJ
authors.lastname: Su
authors.affiliation: Department of Hematology-Oncology, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
authors.forename: Yu-Yi
authors.initials: YY
authors.lastname: Chu
authors.affiliation: College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Lai
authors.affiliation: Department of Gastroenterology-Hepatology, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
authors.forename: Jian-He
authors.initials: JH
authors.lastname: Fang
authors.affiliation: College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Infectious Diseases, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
authors.forename: Ching-Tai
authors.initials: CT
authors.lastname: Huang
authors.affiliation: College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Hematology-Oncology, Linkou Medical Centre, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
authors.forename: Yung-Chang
authors.initials: YC
authors.lastname: Lin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D053804:Granzymes / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D019394:Ki-67 Antigen / Q000235:genetics / Q000276:immunology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000235:genetics* / Q000276:immunology; D054353:Perforin / Q000235:genetics / Q000276:immunology; D011498:Protein Precursors / Q000235:genetics* / Q000276:immunology; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor; C584933:CCR5 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D019394:Ki-67 Antigen; D010455:Peptides; D011498:Protein Precursors; D019713:Receptors, CCR5; D047889:Receptors, Tumor Necrosis Factor, Type II; D016212:Transforming Growth Factor beta; C472416:latency-associated propeptide, TGF-beta; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes