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A Unique Subset of CD4⁺CD25^highFoxp3⁺ T Cells Secreting Interleukin-10 and Transforming Growth Factor-ß1 Mediates Suppression in the Tumor Microenvironment

Authors' Affiliations: ¹ University of Pittsburgh Cancer Institute and Departments of ² Pathology, ³ Immunology, and ⁴ Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Requests for reprints: Theresa L. Whiteside, University of Pittsburgh Cancer Institute, Research Pavilion at the Hillman Cancer Center, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213-1863. Phone: 412-624-0096; Fax: 412-624-0264; E-mail: whitesidetl{at}upmc.edu.

Purpose: Immunosuppression, including that mediated by CD4⁺CD25^highFoxp3⁺ regulatory T cells (Treg), is a characteristic feature of head and neck squamous cell carcinoma (HNSCC). Tregs with a distinct phenotype in tumor-infiltrating lymphocytes (TIL) contribute to local immune suppression.

Experimental Design: The frequency and phenotype of Treg in TIL and/or peripheral blood mononuclear cells (PBMC) in 15 HNSCC patients and PBMC in 15 normal controls were compared. Single-cell sorted CD4⁺CD25^high T cells were tested for regulatory function by coculture with carboxyfluorescein diacetate succinimidyl ester–labeled and activated autologous CD4⁺CD25^– responder T cells. Transwell inserts separating Treg from responders and neutralizing interleukin-10 (IL-10) or transforming growth factor-ß1 (TGF-ß1) antibodies were used to evaluate the mechanisms used by Treg to suppress responder cell proliferation.

Results: In TIL, CD25⁺ cells were enriched in the CD3⁺CD4⁺ subset (13 ± 3%) relative to circulating CD3⁺CD4⁺ T cells (3 ± 0.7%) in HNSCC patients (P 0.01) or normal controls (2 ± 1.5%; P 0.001). Among the CD3⁺CD4⁺ subset, CD25^high Treg represented 3 ± 0.5% in TIL, 1 ± 0.3% in PBMC, and 0.4 ± 0.2% in normal controls. Tregs in TIL were GITR⁺, IL-10⁺, and TGF-ß1⁺, although circulating Treg up-regulated CD62L and CCR7 but not GITR, IL-10, or TGF-ß1. Treg in TIL mediated stronger suppression (P 0.001) than Treg in PBMC of HNSCC patients. The addition of neutralizing IL-10 and TGF-ß antibodies almost completely abrogated suppression (5 ± 2.51%). Transwell inserts partly prevented suppression (60 ± 5% versus 95 ± 5%).

Conclusions: Suppression in the tumor microenvironment is mediated by a unique subset of Treg, which produce IL-10 and TGF-ß1 and do not require cell-to-cell contact between Treg and responder cells for inhibition.

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