title: Cathepsin S inhibition changes regulatory T-cell activity in regulating bladder cancer and immune cell proliferation and apoptosis.
abstract: Regulatory T cells (Tregs) are immune suppressive cells, but their roles in tumor growth have been elusive, depending on tumor type or site. Our prior study demonstrated a role of cathepsin S (CatS) in reducing Treg immunosuppressive activity. Therefore, CatS inhibition in Tregs may exacerbate tumor growth. Using mouse bladder carcinoma MB49 cell subcutaneous implant tumor model, we detected no difference in tumor growth, whether mice were given saline- or CatS inhibitor-treated Tregs. However, mice that received inhibitor-treated Tregs had fewer splenic and tumor Tregs, and lower levels of tumor and splenic cell proliferation than mice that received saline-treated Tregs. In vitro, inhibitor-treated Tregs showed lower proliferation and higher apoptosis than saline-treated Tregs when cells were exposed to MB49. In contrast, both types of Tregs showed no difference in proliferation when they were co-cultured with normal splenocytes. Inhibitor-treated Tregs had less apoptosis in splenocytes, but more apoptosis in splenocytes with MB49 conditioned media than saline-treated Tregs. In turn, we detected less proliferation and more apoptosis of MB94 cells after co-culture with inhibitor-treated Tregs, compared with saline-treated Tregs. B220+B-cell, CD4+T-cell, and CD8+T-cell proliferation and apoptosis were also lower in splenocytes co-cultured with inhibitor-treated Tregs than with saline-treated Tregs. Under the same conditions, the addition of cancer cell-conditioned media greatly increased CD8+T-cell proliferation and reduced CD8+T-cell apoptosis. These observations suggest that CatS inhibition of Tregs may reduce overall T-cell immunity under normal conditions, but enhance CD8+T-cell immunity in the presence of cancer cells.
authors.affiliation: Department of Urology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan, 430022, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marcela M
authors.initials: MM
authors.lastname: Santos
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Cong-Lin
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chongzhe
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Liao
authors.affiliation: Department of Urology, Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China.
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: gshi@rics.bwh.harvard.edu.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002295:Carcinoma, Transitional Cell / Q000276:immunology* / Q000473:pathology; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D057056:Cysteine Proteases / Q000494:pharmacology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000473:pathology
chemical_list: D002403:Cathepsins; D057056:Cysteine Proteases; C028217:cathepsin S
keywords: Apoptosis; Bladder cancer; Cathepsin S; Proliferation; Regulatory T-cell; Splenocytes