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The Wilms' Tumor Antigen Is a Novel Target for Human CD4⁺ Regulatory T Cells: Implications for Immunotherapy

¹ Tumor Immunology Section, ² Histocompatibility and Immunogenetics Section, ³ Adult Hematology/Oncology, and ⁴ Immunopathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Requests for reprints: Said Dermime, Tumor Immunology Section, King Faisal Specialist Hospital and Research Centre, MBC 03, P. O. Box 3354, Riyadh 11211, Saudi Arabia. Phone: 966-1-442-4552; Fax: 966-1-442-7858; E-mail: Sdermime{at}kfshrc.edu.sa or sdermime{at}gmail.com.

Key Words: WT1 antigen • regulatory T cells • CD4⁺CD25⁺Foxp3⁺ • Leukemia • T helper phenotype

Compelling evidences indicate a key role for regulatory T cells (T_reg) on the host response to cancer. The Wilms' tumor antigen (WT1) is overexpressed in several human leukemias and thus considered as promising target for development of leukemia vaccine. However, recent studies indicated that the generation of effective WT1-specific cytotoxic T cells can be largely affected by the presence of T_regs. We have generated T-cell lines and clones that specifically recognized a WT1-84 (RYFKLSHLQMHSRKH) peptide in an HLA-DRB1*0402–restricted manner. Importantly, they recognized HLA-DRB1*04–matched fresh leukemic cells expressing the WT1 antigen. These clones exerted a T helper 2 cytokine profile, had a CD4⁺CD25⁺Foxp3⁺GITR⁺CD127^– T_reg phenotype, and significantly inhibited the proliferative activity of allogeneic T cells independently of cell contact. Priming of alloreactive T cells in the presence of T_regs strongly inhibited the expansion of natural killer (NK), NK T, and CD8⁺ T cells and had an inhibitory effect on NK/NK T cytotoxic activity but not on CD8⁺ T cells. Furthermore, priming of T cells with the WT1-126 HLA-A0201–restricted peptide in the presence of T_regs strongly inhibited the induction of anti–WT1-126 CD8⁺ CTL responses as evidenced by both very low cytotoxic activity and IFN- production. Moreover, these T_reg clones specifically produced granzyme B and selectively induced apoptosis in WT1-84–pulsed autologous antigen-presenting cells but not in apoptotic-resistant DR4-matched leukemic cells. Importantly, we have also detected anti–WT1-84 interleukin-5⁺/granzyme B⁺/Foxp3⁺ CD4⁺ T_regs in five of eight HLA-DR4⁺ acute myeloid leukemia patients. Collectively, our in vitro and in vivo findings strongly suggest important implications for the clinical manipulation of T_regs in cancer patients. [Cancer Res 2008;68(15):6350–9]