title: Combination of tumor site-located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses.
abstract: Accumulating data indicate that tumor-infiltrating regulatory T cells (Treg) are present in human tumors and locally suppress antitumor immune cells. In this study, we found an increased Treg/CD8 ratio in human breast and cervical cancers. A similar intratumoral lymphocyte pattern was observed in a mouse model for cervical cancer (TC-1 cells). In this model, systemic Treg depletion was inefficient in controlling tumor growth. Furthermore, systemic CTL-associated antigen-4 (CTLA-4) blockade, an approach that can induce tumor immunity in other tumor models, did not result in TC-1 tumor regression but led to spontaneous development of autoimmune hepatitis. We hypothesized that continuous expression of an anti-CTLA-4 antibody localized to the tumor site could overcome Treg-mediated immunosuppression and locally activate tumor-reactive CD8+ cells, without induction of autoimmunity. To test this hypothesis, we created TC-1 cells that secrete a functional anti-CTLA-4 antibody (TC-1/alphaCTLA-4-gamma1 cells). When injected into immunocompetent mice, the growth of TC-1/alphaCTLA-4-gamma1 tumors was delayed compared with control TC-1 cells and accompanied by a reversion of the intratumoral Treg/CD8 ratio due to an increase in tumor-infiltrating IFNgamma-producing CD8+ cells. When local anti-CTLA-4 antibody production was combined with Treg inhibition, permanent TC-1 tumor regression and immunity was induced. Importantly, no signs of autoimmunity were detected in mice that received local CTLA-4 blockade alone or in combination with Treg depletion.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Tuve
authors.forename: Bing-Mae
authors.initials: BM
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Tian-Lu
authors.initials: TL
authors.lastname: Cheng
authors.forename: Papa
authors.initials: P
authors.lastname: Touré
authors.forename: Papa Salif
authors.initials: PS
authors.lastname: Sow
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Feng
authors.forename: Nancy
authors.initials: N
authors.lastname: Kiviat
authors.forename: Robert
authors.initials: R
authors.lastname: Strauss
authors.forename: Shaoheng
authors.initials: S
authors.lastname: Ni
authors.forename: Zong-Yi
authors.initials: ZY
authors.lastname: Li
authors.forename: Steve R
authors.initials: SR
authors.lastname: Roffler
authors.forename: André
authors.initials: A
authors.lastname: Lieber
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D060908:CTLA-4 Antigen; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008212:Lymphocyte Depletion; D016131:Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D002583:Uterine Cervical Neoplasms / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse