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Treatment-Enhanced CD4⁺Foxp3⁺ Glucocorticoid-Induced TNF Receptor Family Related^High Regulatory Tumor-Infiltrating T Cells Limit the Effectiveness of Cytokine-Based Immunotherapy¹

Aklile Berhanu^2,*, Jian Huang^2,*, Simon C. Watkins, Hideho Okada^,¶ and Walter J. Storkus^3,*,,¶

^* Department of Immunology, Department of Cell Biology and Molecular Physiology, Department of Surgery, and Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and ^¶ University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213

Regulatory T cells can suppress activated CD4⁺ and CD8⁺ T effector cells and may serve as an impediment to spontaneous or therapeutic type 1 antitumor immunity. In a previous study, we observed minimal therapeutic impact, but significantly enhanced T cell cross-priming and lesional infiltration of tumor-reactive CD8⁺ T cells into established CMS4 sarcomas after combined treatment of BALB/c mice with rFLt3 ligand (rFL) and recombinant GM-CSF (rGM-CSF). In this study, we show that this cytokine regimen also results in the profound enhancement of CD4⁺ tumor-infiltrating lymphocytes (TIL) expressing FoxP3, IL-10, and TGF- mRNA, with 50 or 90% of CD4⁺ TIL coexpressing the CD25 and glucocorticoid-induced TNFR family related molecules, respectively. Intracellular staining for Foxp3 protein revealed that combined treatment with rFL plus rGM-CSF results in a significant increase in CD4⁺Foxp3⁺ T cells in the spleen of both control and tumor-bearing mice, and that nearly half of CD4⁺ TIL expressed this marker. In addition, CD4⁺ TIL cells were of an activated/memory (ICOS^highCD62L^lowCD45RB^low) phenotype and were capable of suppressing allospecific T cell proliferation and IFN- production from (in vivo cross-primed) anti-CMS4 CD8⁺ T cells in vitro, via a mechanism at least partially dependent on IL-10 and TGF-. Importantly, in vivo depletion of CD4⁺ T cells resulted in the ability of previously ineffective, rFL plus rGM-CSF therapy-induced CD8⁺ T cells to now mediate tumor regression.

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 R01 Grant CA63350 (to W.J.S.).

² A.B. and J.H. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Walter J. Storkus, Departments of Dermatology and Immunology, W1041 Biomedical Sciences Tower, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail address: storkuswj{at}upmc.edu

⁴ Abbreviations used in this paper: Treg, regulatory T cell; DC, dendritic cell; GITR, glucocorticoid-induced TNFR family related; MFI, median fluorescence intensity; rFL, rFLt3 ligand; rGM-CSF, recombinant GM-CSF; TIDC, tumor-infiltrating DC; TIL, tumor-infiltrating lymphocyte; WB, wash buffer.

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