AuthOr’s VIew AuthOr’s VIew Figure 1. Proposed model for amplification of t regs after castration. s urgical castration induces apoptotic death of cancerous prostate epithelium. Antigens shed by the dying prostate tumor elicit effector CD8+ t -cell responses, which induce production of IL-2 by effector t cells. Preferential con - sumption of IL-2 by t regs leads to t reg expansion and subsequent inhibition of CD8+ t -cell function in the prostate draining lymph nodes (PDLN). Increased IL-2 produced by the acti- vated effector T cells leads to expansion of Tregs, which then inhibit CD8+ T-cell function.8,9 This paracrine loop is at least partially responsible for prostate cancer progression after castration. It is possible that androgen ablation may also change Treg homeostasis through modulation of thymic T-cell development, contributing to Treg expansion after immunization. We depleted Tregs by administration of anti-CD25 antibody 2 d prior to castration. A limitation of this therapy is the potential collateral elimination of CD25+ effector T cells. In our system, however, anti-CD25 treatment augmented CD8+ effector cell function. We speculate that the availability of IL-2 as a result of Treg depletion height- ens effector T-cell proliferation, compen- sating for an initial depletion of CD25+ effector T cells. Alternately, only CD25hi T cells, which may be predominantly Tregs, are depleted by anti-CD25 admin- istration.10 Importantly, Tregs were ampli- fied after castration only when immune responses against tumor antigens were also induced, and not when wild-type animals were castrated alone, further strengthening the suggestion that increased IL-2 caused the paradoxical response. Our results imply that other treatments such as chemotherapy or radiation ther- apy, which also induce massive tumor cell death, can expand both effector T cells and Tregs. Treg depletion prior to or along with tumoridical therapy may augment effector anti-tumor immune responses, preventing tumor progression and devel- opment of metastatic disease. 1. 2. References Mercader M, Bodner BK, Moser MT, Kwon PS, Park ES, Manecke RG, et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad Sci USA 2001; 98:14565-70; PMID:11734652; http://dx.doi. org/10.1073/pnas.251140998. Drake CG, Doody AD, Mihalyo MA, Huang CT, Kelleher E, Ravi S, et al. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted anti- gen. Cancer Cell 2005; 7:239-49; PMID:15766662; http://dx.doi.org/10.1016/j.ccr.2005.01.027. 3. Aragon-Ching JB, Williams KM, Gulley JL. Impact of androgen-deprivation therapy on the immune system: implications for combination therapy of prostate can- cer. Front Biosci 2007; 12:4957-71; PMID:17569623; http://dx.doi.org/10.2741/2441. 4. Ansar Ahmed S, Penhale WJ, Talal N. Sex hor- mones, immune responses and autoimmune diseases. Mechanisms of sex hormone action. Am J Pathol 1985; 121:531-51; PMID:3907369. 5. Akins EJ, Moore ML, Tang S, Willingham MC, Tooze JA, Dubey P. In situ vaccination combined with andro- gen ablation and regulatory T-cell depletion reduces castration-resistant tumor burden in prostate-specific pten knockout mice. Cancer Res 2010; 70:3473-82; PMID:20406970; http://dx.doi.org/10.1158/0008- 5472.CAN-09-2490. 6. Tang S, Moore ML, Grayson JM, Dubey P. Increased CD8+ T-cell Function following Castration and Immunization Is Countered by Parallel Expansion of Regulatory T Cells. Cancer Res 2012; 72:1975-85; PMID:22374980; http://dx.doi.org/10.1158/0008- 5472.CAN-11-2499. 7. Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 2010; 33:153-65; PMID:20732639; http:// dx.doi.org/10.1016/j.immuni.2010.08.004. 8. McNally A, Hill GR, Sparwasser T, Thomas R, Steptoe RJ. CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis. Proc Natl Acad Sci USA 2011; 108:7529- 34; PMID:21502514; http://dx.doi.org/10.1073/ pnas.1103782108. 9. Kastenmuller W, Gasteiger G, Subramanian N, Sparwasser T, Busch DH, Belkaid Y, et al. Regulatory T cells selectively control CD8+ T cell effector pool size via IL-2 restriction. J Immunol 2011; 187:3186-97; PMID:21849683; http://dx.doi.org/10.4049/jimmu- nol.1101649. 10. Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 2005; 115:3623- 33; PMID:16308572; http://dx.doi.org/10.1172/ JCI25947. www.landesbioscience.com OncoImmunology 1221