Combination of Tumor Site–Located CTL-Associated Antigen-4 Blockade and Systemic Regulatory T-Cell Depletion Induces Tumor-Destructive Immune Responses
Cancer Res 2007;67(12):5929–39
Sebastian Tuve1, Bing-Mae Chen3, Ying Liu1, Tian-Lu Cheng4, Papa Touré5, Papa Salif Sow5, Qinghua Feng2, Nancy Kiviat2, Robert Strauss1, Shaoheng Ni1, Zong-Yi Li1, Steve R. Roffler3 and André Lieber1,2
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@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@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/{alpha}CTLA-4-{gamma}1 cells). When injected into immunocompetent mice, the growth of TC-1/{alpha}CTLA-4-{gamma}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{gamma}-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. |
