AuthOr’s VIew OncoImmunology 1:7, 1220-1221; October 2012; © 2012 Landes Bioscience Opposing effects of androgen ablation on immune function in prostate cancer shuai t ang1 and Purnima Dubey2,3,4,5,6,* 1Molecular Pathology Graduate Program; wake Forest school of Medicine; w inston salem, NC us A; 2Department of Pathology-tumor Biology; wake Forest school of Medicine; w inston salem, NC us A; 3Department of Cancer Biology; wake Forest school of Medicine; w inston salem, NC us A; 4Department of Microbiology & Immunology; wake Forest school of Medicine; w inston salem, NC us A; 5Molecular Medicine and t ranslational science Program; wake Forest school of Medicine; w inston salem, NC us A; 6Comprehensive Cancer Center; wake Forest school of Medicine; w inston salem, NC us A Keywords: prostate cancer, androgen ablation, Tregs, castration-resistant, CD8+ effector T cells Although it is recognized that immune function is modulated by androgen ablation therapy for prostate cancer, the long-term consequences are not completely understood. we recently showed that both effector and inhibitory immune mechanisms are amplified by androgen ablation, providing one explanation for only transient increases in immune function after castration. Androgen ablation is a first-line therapy for advanced prostate cancer, and results in apoptotic death of the primary tumor. Studies of immune function early after androgen ablation showed that hormone removal increased T-cell responses to pros- tate tumor antigens.1,2 However, immune augmentation must be transient, since castration-resistant disease recurs, months to years after treatment of the primary tumor. Thus, understanding the long- term impact of androgen ablation/block- ade on the immune system will permit the development of more effective immune therapies for advanced prostate cancer. The mechanisms for increased T-cell responses after castration are not com- pletely understood. Androgen ablation increases thymus size and peripheral T-cell numbers (reviewed in ref. 3), sug- gesting that heightened responses may be due to greater numbers of naive T cells capable of responding to tumor antigens. Subsequent studies in autoimmune dis- ease models have shown that hormone blockade/removal ameliorates autoim- mune disease, suggesting that inhibitory immune mechanisms that control effector responses may also be increased (reviewed in ref. 4). In the context of prostate cancer, pre- clinical and clinical studies have shown that CD4+ and CD8+ T-cell responses are increased early after androgen ablation.1 Functional CD8+ cytolytic T cells are required for the rejection of solid tumors. In a murine model of endogenous pros- tate cancer generated by prostate-specific deletion of the Pten tumor suppressor gene, we observed that functional CD8+ T-cell numbers were increased at an early time point after surgical castration, but declined rapidly to pre-castration levels.5 Building on these data and the observa- tions of ameliorated autoimmune disease after androgen ablation, we hypothesized that immune inhibitory mechanisms must be amplified after castration as well. In our recent work, we found that the numbers of CD4+CD25+FoxP3+ regula- tory T cells (Tregs) were amplified in the prostate draining lymph node and spleen of castrated Pten-/- mice compared with sham-castrated Pten-/- mice.6 This increase was observed at an early time point (2.5 weeks) post-castration, when functional GzB+/CD8+ T cells in the prostate tumor were also increased in number. To deter- mine whether increased Tregs affected CD8+ T-cell responses to a defined tumor antigen, we immunized Pten-/- mice with the model tumor cell line, UV8101-RE. Heightened responses to this antigen were only observed when Tregs were also depleted together with castration. Increased functional antigen-specific CD8+ T cells were maintained for several weeks (5 weeks post-castration) in the LN and spleen, demonstrating that Treg deple- tion both increased and sustained effector T-cell function. These data suggest that increased Tregs may prevent the mainte- nance of CD8+ T-cell responses to prostate tumor antigens shed by the dying primary prostate tumor, and may be one mecha- nism responsible for only transient increase in effector function after castration. It is presumed that the dying prostate epithelial cells shed previously sequestered tumor antigens which then activate CD8+ and CD4+ T cells, leading to secretion of effector cytokines such as interleukin-2 (IL-2) by the T cells. In addition to sup- porting effector T-cell proliferation and differentiation, IL-2 is the signature cyto- kine required for the maintenance and expansion of Tregs.7 We showed that in vivo blockade of IL-2 together with cas- tration of Pten-/- mice prevented Treg expansion. Together, our results suggest the following model (Fig. 1): surgical castration causes apoptosis of hormone dependent cancerous prostate epithelium, leading to processing and presentation of shed tumor antigens, and amplification of functional CD8+ T cells within the tumor. *Correspondence to: Purnima Dubey; Email: pdubey@wakehealth.edu Submitted: 04/18/12; Accepted: 04/20/12 http://dx.doi.org/10.4161/onci.20448 1220 OncoImmunology Volume 1 Issue 7