title: Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance.
abstract: Thymic central tolerance is a critical process that prevents autoimmunity but also presents a challenge to the generation of anti-tumor immune responses. Medullary thymic epithelial cells (mTECs) eliminate self-reactive T cells by displaying a diverse repertoire of tissue-specific antigens (TSAs) that are also shared by tumors. Therefore, while protecting against autoimmunity, mTECs simultaneously limit the generation of tumor-specific effector T cells by expressing tumor self-antigens. This ectopic expression of TSAs largely depends on autoimmune regulator (Aire), which is expressed in mature mTECs. Thus, therapies to deplete Aire-expressing mTECs represent an attractive strategy to increase the pool of tumor-specific effector T cells. Recent work has implicated the TNF family members RANK and RANK-Ligand (RANKL) in the development of Aire-expressing mTECs. We show that in vivo RANKL blockade selectively and transiently depletes Aire and TSA expression in the thymus to create a window of defective negative selection. Furthermore, we demonstrate that RANKL blockade can rescue melanoma-specific T cells from thymic deletion and that persistence of these tumor-specific effector T cells promoted increased host survival in response to tumor challenge. These results indicate that modulating central tolerance through RANKL can alter thymic output and potentially provide therapeutic benefit by enhancing anti-tumor immunity.
authors.affiliation: Diabetes Center and 2 Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Imran S
authors.initials: IS
authors.lastname: Khan
authors.forename: Maria L
authors.initials: ML
authors.lastname: Mouchess
authors.forename: Meng-Lei
authors.initials: ML
authors.lastname: Zhu
authors.forename: Bridget
authors.initials: B
authors.lastname: Conley
authors.forename: Kayla J
authors.initials: KJ
authors.lastname: Fasano
authors.forename: Yafei
authors.initials: Y
authors.lastname: Hou
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Su
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D015551:Autoimmunity / Q000276:immunology*; D061167:Central Tolerance / Q000187:drug effects / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics; D007211:Indoles; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000276:immunology*; D053244:Osteoprotegerin / Q000235:genetics; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism; D000096927:AIRE Protein
chemical_list: D000951:Antigens, Neoplasm; D018398:Homeodomain Proteins; D007211:Indoles; D053244:Osteoprotegerin; D053245:RANK Ligand; D014157:Transcription Factors; D000096927:AIRE Protein; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; C064658:RAG-1 protein; C007293:DAPI
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