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Combination of Tumor Site–Located CTL-Associated Antigen-4 Blockade and Systemic Regulatory T-Cell Depletion Induces Tumor-Destructive Immune Responses

¹ Division of Medical Genetics, Department of Medicine and ² Department of Pathology, University of Washington, Seattle, Washington; ³ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; ⁴ Faculty of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan; and ⁵ Department of Infectious Diseases, University of Dakar, Dakar, Senegal

Requests for reprints: André Lieber, University of Washington, Box 357720, Seattle, WA 98195. Phone: 206-221-3973; Fax: 206-685-8675; E-mail: lieber00{at}u.washington.edu and Steve Roffler, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan. Phone: 886-2-2652-3079; Fax: 886-2-2782-9142; E-mail: sroff{at}ibms.sinica.edu.tw.

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/CTLA-4-1 cells). When injected into immunocompetent mice, the growth of TC-1/CTLA-4-1 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 IFN-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. [Cancer Res 2007;67(12):5929–39]

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