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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Combination of tumor site-located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor-destructive immune responses
Cancer Research, Volume 67, No. 12, Year 2007
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Description
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/αCTLA-4-γ1 cells). When injected into immunocompetent mice, the growth of TC-1/αCTLA-4-γ1 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 IFNγ-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. ©2007 American Association for Cancer Research.
Authors & Co-Authors
Tuve, Sebastian
United States, Seattle
University of Washington
Chen, Bingmae
Taiwan, Taipei
Academia Sinica, Institute of Biomedical Sciences
Liu, Ying
United States, Seattle
University of Washington
Cheng, Tianlu
Taiwan, Kaohsiung
Kaohsiung Medical University
Touré, Papa Souleymane
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Sow, Papa Salif
Senegal, Dakar
Université Cheikh Anta Diop de Dakar
Feng, Quinghua
United States, Seattle
University of Washington
Kiviat, Nancy B.
United States, Seattle
University of Washington
Strauss, Robert
United States, Seattle
University of Washington
Ni, Shaoheng
United States, Seattle
University of Washington
Li, Zongyi
United States, Seattle
University of Washington
Roffler, Steve R.
Taiwan, Taipei
Academia Sinica, Institute of Biomedical Sciences
Lieber, André
United States, Seattle
University of Washington
Statistics
Citations: 97
Authors: 13
Affiliations: 4
Identifiers
Doi:
10.1158/0008-5472.CAN-06-4296
ISSN:
00085472
Research Areas
Cancer
Infectious Diseases