title: CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients.
abstract: Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent anti-CTLA-4 antibody. All clinical trials to date, comprising over 3,000 patients, have been conducted in the metastatic disease setting, which allows for correlation of drug administration with clinical outcome but has limited analyses of intermediate biomarkers to indicate whether the drug has impacted human immune responses within the tumor microenvironment. We conducted a pre-surgical clinical trial in six patients with localized bladder cancer, which allowed for correlation of drug administration with biomarkers in both blood and tumor tissues but did not permit correlation with clinical outcome. We found that CD4 T cells from peripheral blood and tumor tissues of all treated patients had markedly increased expression of inducible costimulator (ICOS). These CD4(+)ICOS(hi) T cells produced IFN-gamma (IFNgamma) and could recognize the tumor antigen NY-ESO-1. Increase in CD4(+)ICOS(hi) cells led to an increase in the ratio of effector to regulatory T cells. To our knowledge, these are the first immunologic changes reported in both tumor tissues and peripheral blood as a result of treatment with anti-CTLA-4 antibody, and they may be used to guide dosing and scheduling of this agent to improve clinical responses.
authors.affiliation: Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
authors.forename: Chrysoula I
authors.initials: CI
authors.lastname: Liakou
authors.forename: Ashish
authors.initials: A
authors.lastname: Kamat
authors.forename: Derek Ng
authors.initials: DN
authors.lastname: Tang
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Jingjing
authors.initials: J
authors.lastname: Sun
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.forename: Christopher
authors.initials: C
authors.lastname: Logothetis
authors.forename: Padmanee
authors.initials: P
authors.lastname: Sharma
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis*; D015704:CD4 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D002277:Carcinoma / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000096:biosynthesis*; D000074324:Ipilimumab; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D000074324:Ipilimumab; D007371:Interferon-gamma