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Depleting Intratumoral CD4⁺CD25⁺ Regulatory T Cells via FasL Protein Transfer Enhances the Therapeutic Efficacy of Adoptive T Cell Transfer

¹ Department of Biomedical Sciences, College of Medicine at Rockford, University of Illinois, Rockford, Illinois; ² Department of Histology and Embryology, Second Military Medical University, Shanghai, China; and ³ State Key Lab for Agro-Biotechnology, China Agricultural University, Beijing, China

Requests for reprints: Aoshuang Chen or Guoxing Zheng, Department of Biomedical Sciences, College of Medicine at Rockford, University of Illinois, 1601 Parkview Avenue, Rockford, IL 61107. Phone: 815-395-5680; Fax: 815-395-5666; E-mail: aoshuang{at}uic.edu or guoxingz{at}uic.edu.

One strategy for improving adoptive therapy is preconditioning the host immune environment by depleting CD4⁺CD25⁺ regulatory T cells (Treg) suppressive to antitumor responses. Given that Treg increase, or selectively accumulate, within tumors and are sensitive to FasL-mediated apoptosis, we test here the hypothesis that inducing apoptosis of intratumoral Treg using FasL may improve adoptive T cell therapy. We show that FasL applied intratumorally via protein transfer decreases intratumoral Treg via inducing apoptosis in these cells. Significantly, we show that the use of FasL prior to the infusion of tumor-reactive CD8⁺ T cells enhances the therapeutic efficacy of adoptive T cell transfer against established tumors, which is mediated by persistent, systemic antitumor immunity. Intratumoral FasL protein transfer also results in neutrophil infiltration of tumor. However, we show that intratumoral immunodepletion of neutrophils does not abolish the effect of FasL on adoptive transfer. Rather, the effect of FasL is completely abolished by cotransfer of Treg, isolated from the tumor-draining lymph nodes. Hence, our study shows for the first time that using FasL to predeplete intratumoral Treg provides a useful means for optimizing adoptive therapy. [Cancer Res 2007;67(3):1291–8]

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