function; but they become suppressive after culture with tumor- derived factors, which is corroborated by the fact that MDSC from tumor tissue rather than spleen possess the suppressive character- istics. In these studies, the authors claimed that the regaining of suppressive function was because these MDSC differentiated into suppressive macrophages (F4/80+) [35,39,40]. In our report, resveratrol administration recovered their suppressive functional- ities including the expression of Arg1, the suppression of the proliferation and cytotoxicity of LAK cells, as well as suppression of the development of VLS after the adoptive transfer (Fig. 8A– 8D). Whether resveratrol can induce the differentiation of the suppressive macrophages or how resveratrol recoveres the suppressive function of MDSC is not clear. We examined the interaction between resveratrol and MDSC. AhR functions as one the main receptors for resveratrol [23]. Our results demonstrated that resveratrol could induce the expression of AhR in the MDSC while IL-2 could not. Interestingly, IL-2 and resveratrol co- treatment induced the most expression of AhR (Fig. 8E). This could be because resveratrol is more effective in activated cells than unactivated cells [30]. We noted that the expression of AhR was positively related to the expression level of Arg1 and suppression functionality of MDSC. IL-MDSC showed the lowest level of AhR whereas R-MDSC showed the highest level of AhR. We assume that the signals from AhR may be critical for MDSCs to recover their function. The signals from AhR-resveratrol reaction might act as a mimic to the tumor-derived signals that induce the suppressive function of MDSCs. Further studies are needed to clarify this hypothesis. Resveratrol has been shown to possess chemopreventive activities such as suppression of tumor cell proliferation, induction of tumor cell apoptosis, and enhancement of chemosensitization of tumor cells [21,22,24,25]. It is known that resveratrol can directly induce cell-cycle disruption and apoptosis in chemoresistant B16 melanoma that leads to tumor regresson; meanwhile, resveratrol makes melanomas more susceptible to the chemotherapeutic drugs [24,25]. Our results showed: (1) resveratrol significantly enhanced the expression of FoxO1 gene of melanoma (Fig. 9A-9C). (2) resveratrol dramatically increased the susceptibility of melanoma References 1. Dutcher J (2002) Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma. Oncology (Williston Park) 16: 4–10. 2. Schwartz RN, Stover L, Dutcher J (2002) Managing toxicities of high-dose interleukin-2. Oncology (Williston Park) 16: 11–20. 3. 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(2004) NK cells and polymorphonuclear neutrophils are both critical for IL-2-induced pulmonary vascular leak syndrome. J Immunol 172: 7661–7668. 9. Damle NK, Doyle LV (1989) IL-2-activated human killer lymphocytes but not their secreted products mediate increase in albumin flux across cultured endothelial monolayers. Implications for vascular leak syndrome. J Immunol 142: 2660–2669. 10. Rosenstein M, Ettinghausen SE, Rosenberg SA (1986) Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2. J Immunol 137: 1735–1742. Resveratrol in IL-2 Therapy against Melanoma to LAK cytotoxicity (Fig. 9D). It is known that FoxO1 controls the tumor growth; the expression of FoxO1 inhibits the tumor growth and triggers the ultimate death of tumor [31,32]. We propose that the above two effects of resveratrol might compensate and overcome the suppression of MDSC on the tumor infiltrating T lymphocytes so as to promote anti-tumor immunity. The response to immunotherapy with HDIL-2 in patients with metastatic RCC and melanoma is about 15% to 23%. The immune suppression caused by the HDIL-2 treatment, such as induction of Tregs, could be part of the reason why HDIL-2 remains less effective [1,2,3,4,5,37,38]. Our results indicate that induction of MDSC is also an important factor in affecting the results of the treatment. The functional status of immune suppression of MDSC could be related to the responsiveness of the therapy in patients. The clinical evidence is needed to further elucidate such an issue. Resveratrol could be act in two beneficial ways in HDIL-2 therapy by suppressing endothelial damage while enhancing sensitivity of tumor killing. In our previous studies, we have shown that melanoma cells and ECs can show differential susceptibility to LAK lysis based on the expression of CD44 variant isoforms [27]. 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