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* Laboratory of Molecular and Tumor Immunology and
Immunological Monitoring Laboratory, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center and Providence Portland Medical Center, Portland, OR 97213; and
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97201
Regulatory T (Treg) cells represent a major roadblock to the induction of antitumor immunity through vaccine approaches. TGF-β is a cytokine implicated in the generation and maintenance of Treg cells, as well as in their suppressive function. These experiments examined whether the generation of tumor-sensitized Treg cells was TGF-β dependent and evaluated whether TGF-β produced by Treg cells blocked the priming of tumor-specific T cells in vaccinated reconstituted lymphopenic mice. We show that tumor-sensitized Treg cells (CD25+/FoxP3+) obtained from tumor-bearing mice block the generation of tumor-specific T cells in reconstituted lymphopenic mice. Strikingly, this suppression is absent if tumor-sensitized Treg cells are acquired from tumor-bearing mice expressing the dominant-negative TGFβRII in T cells. This loss of suppression was a result of the crucial role of TGF-β in generating tumor-sensitized Treg cells, and not due to the insensitivity of naive or tumor-primed effector T cells to the direct suppressive influence of TGF-β. We conclude that blocking TGF-β in a tumor-bearing host can inhibit the induction of highly suppressive tumor-sensitized Treg cells. These data suggest that an integrative strategy combining "up-front" Treg cell ablation followed by vaccination and TGF-β blockade may limit generation of new tumor-sensitized Treg cells and improve the generation of therapeutic immune responses in patients with cancer.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant RO1 CA80964, the Chiles Foundation, Robert W. Franz, the Providence Medical Foundation, and the Murdock Trust.
2 Address correspondence and reprint requests to Dr. Bernhard Fox, Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, 4805 NE Glisan Street, Portland, OR 97213. E-mail address: foxb{at}foxlab.org
3 Abbreviations used in this paper: Treg cell, regulatory T cell; CM, complete medium; dnTGFβRII, dominant-negative TGF-βR type II; RLM, reconstituted lymphopenic mouse; TBM, tumor-bearing mouse; TVDLN, tumor vaccine draining lymph node; WT, wild type.
This article has been cited by other articles:
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  M. G. LaCelle, S. M. Jensen, and B. A. Fox Partial CD4 Depletion Reduces Regulatory T Cells Induced by Multiple Vaccinations and Restores Therapeutic Efficacy Clin. Cancer Res., November 15, 2009; 15(22): 6881 - 6890. [Abstract] [Full Text] [PDF]
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