Microenvironment and Immunology Aire De fi ciency Promotes TRP-1 – Speci fi c Immune Rejection of Melanoma

The thymic transcription factor autoimmune regulator (Aire) prevents autoimmunity in part by promoting expression of tissue-specific self-antigens, which include many cancer antigens. For example, AIRE-deficient patients are predisposed to vitiligo, an autoimmune disease of melanocytes that is often triggered by efficacious immunotherapies against melanoma. Therefore, we hypothesized that Aire deficiency in mice may elevate immune responses to cancer and provide insights into how such responses might be triggered. In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TYRP1), which is a self-antigen in melanocytes and a cancer antigen in melanomas. Aire deficiency resulted in defective negative selection of TRP-1–specific T cells without affecting thymic numbers of regulatory T cells. Aire-deficient mice displayed elevated T-cell immune responses that were associatedwith suppression ofmelanoma outgrowth. Furthermore, transplantation of Aire-deficient thymic stroma was sufficient to confer more effective immune rejection of melanoma in an otherwise Aire wild-type host. Together, our work showed how Aire deficiency can enhance immune responses against melanoma and howmanipulating TRP-1–specific T-cell negative selection may offer a logical strategy to enhance immune rejection of melanoma. Cancer Res; 1–13. 2013 AACR. Introduction Melanoma is the deadliest form of skin cancer and accounts for 5% of cancer deaths in the United States (1). Understanding mechanisms that may limit melanoma development is therefore a significant public health concern. The cellular immune response has the potential to eradicate melanoma cells, and spontaneous regression of melanoma associated with lymphocytic infiltration of tumors has been reported (2, 3). Despite this potential, the immune response is often ineffective, with high rates of melanoma growth occurring in immunocompetent individuals. Furthermore, while immunotherapy for metastaticmelanoma can result in clinical benefit, a complete response occurs in only a small proportion of patients (4). Overcoming immune tolerance to melanoma in otherwise healthy individuals may therefore be important for preventing and treating melanoma. Several antigens targeted by the immune response in melanoma are also antigens in vitiligo, an acquired depigmenting disorder resulting from autoimmune destruction of melanocytes (5–7). Consistent with shared antigens in these 2 immune settings, the development of melanoma is regularly accompanied by vitiligo in a number of animal models (6). In addition, development of vitiligo in patients with advanced melanoma undergoing immunotherapy is associated with improved prognosis (8). This overlap in immune responses to vitiligo and melanoma suggests that factors that result in vitiligo may also enhance the immune response against melanoma. The autoimmune regulator (Aire) gene promotes organspecific immune tolerance and prevents the development of a number of autoimmune diseases including vitiligo. Patients with mutations in Aire have an 18to 36-fold increased risk of developing vitiligo compared with the general population (9), and genetic polymorphisms in Aire have been associated with vitiligo development in a case–control study (10). Within the thymus, Aire upregulates expression of a large number of tissue-specific self-antigens inmedullary thymic epithelial cells (mTEC; refs. 11–13). Ectopic expression of these self-antigens drives the clonal deletion of developing T cells recognizing these antigens with high affinity (14, 15). In addition, Aire may have other functions affecting T-cell tolerance including possible roles in antigen processing/presentation and the development of regulatory T cells (Tregs; refs. 14, 16, 17). The existence of shared vitiligo/melanoma antigens suggests that decreased Aire function in the thymus, in addition to predisposing to vitiligo, may also enhance immune rejection of melanoma. In support of this hypothesis, Aire polymorphisms have been associated with melanoma development in a small case–control study (18). In addition, Aire-deficient mice may have increased memory response to melanoma following immunization with irradiated melanoma cells (19). At the same time, however, recent work also suggests that thymic expression of a cancer-germline antigen only minimally Authors' Affiliations: Department of Pediatrics and Microbiology/Immunology, School of Medicine; and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Corresponding Author: Maureen A. Su, University of North Carolina at Chapel Hill, 3300 Thurston Building CB7280, Chapel Hill, NC 27599. Phone: 919-966-0259; Fax: 919-843-7588; E-mail: masu@email.unc. edu doi: 10.1158/0008-5472.CAN-12-3781 2013 American Association for Cancer Research. Cancer Research www.aacrjournals. org 1 on May 7, 2015. © 2013 American Association for Cancer Research. cancerres.aacrjournals. org Downloaded from Published OnlineFirst January 31, 2013; DOI: 10.1158/0008-5472.CAN-12-3781