title: T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis-associated cancer in mice.
abstract: Nonresolving inflammation is involved in the initiation and progression process of tumorigenesis. Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is known to inhibit acute inflammation but its role in chronic inflammation-associated cancer remains unclear. The role of SHP2 in T cells in dextran sulfate sodium (DSS)-induced colitis and azoxymethane-DSS-induced colitis-associated carcinogenesis was examined using SHP2CD4-/- conditional knockout mice. SHP2 deficiency in T cells aggravated colitis with increased level of pro-inflammatory cytokines including IFN-γ and IL-17A. In contrast, the SHP2CD4-/- mice developed much fewer and smaller tumors than wild type mice with higher level of IFN-γ and enhanced cytotoxicity of CD8+ T cells in the tumor and peritumoral areas. At the molecular level, STAT1 was hyper-phosphorylated in T cells lacking SHP2, which may account for the increased Th1 differentiation and IFN-γ secretion. IFN-γ neutralization or IFN-γ receptor knockout but not IL-17A neutralization, abrogated the anti-tumor effect of SHP2 knockout with lowered levels of perforin 1, FasL and granzyme B. Finally, the expression of granzyme B was negatively correlated with the malignancy of colon cancer in human patients. In conclusion, these findings suggest a new strategy to treat colitis-associated cancer via targeting SHP2.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: GenSheng
authors.initials: G
authors.lastname: Feng
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D001397:Azoxymethane; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D003602:Cytotoxicity, Immunologic; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000201:enzymology / Q000276:immunology*; D018345:Mice, Knockout; D054353:Perforin / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency* / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D059016:Tumor Microenvironment
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C000611649:IFNG protein, mouse; D018836:Inflammation Mediators; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C510467:perforin 1, mouse; D054353:Perforin; D007371:Interferon-gamma; D016264:Dextran Sulfate; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D053804:Granzymes; C509214:Gzmb protein, mouse; D001397:Azoxymethane
keywords: IFN-γ; SHP2; antitumor immunity; colitis-associated cancer; cytotoxic T lymphocyte