title: Adaptive Immunity to Leukemia Is Inhibited by Cross-Reactive Induced Regulatory T Cells.
abstract: BCR-ABL(+) acute lymphoblastic leukemia patients have transient responses to current therapies. However, the fusion of BCR to ABL generates a potential leukemia-specific Ag that could be a target for immunotherapy. We demonstrate that the immune system can limit BCR-ABL(+) leukemia progression although ultimately this immune response fails. To address how BCR-ABL(+) leukemia escapes immune surveillance, we developed a peptide: MHC class II tetramer that labels endogenous BCR-ABL-specific CD4(+) T cells. Naive mice harbored a small population of BCR-ABL-specific T cells that proliferated modestly upon immunization. The small number of naive BCR-ABL-specific T cells was due to negative selection in the thymus, which depleted BCR-ABL-specific T cells. Consistent with this observation, we saw that BCR-ABL-specific T cells were cross-reactive with an endogenous peptide derived from ABL. Despite this cross-reactivity, the remaining population of BCR-ABL reactive T cells proliferated upon immunization with the BCR-ABL fusion peptide and adjuvant. In response to BCR-ABL(+) leukemia, BCR-ABL-specific T cells proliferated and converted into regulatory T (Treg) cells, a process that was dependent on cross-reactivity with self-antigen, TGF-β1, and MHC class II Ag presentation by leukemic cells. Treg cells were critical for leukemia progression in C57BL/6 mice, as transient Treg cell ablation led to extended survival of leukemic mice. Thus, BCR-ABL(+) leukemia actively suppresses antileukemia immune responses by converting cross-reactive leukemia-specific T cells into Treg cells.
authors.affiliation: Center for Immunology, University of Minnesota, Minneapolis, MN 55455; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Luke S
authors.identifier: http://orcid.org/0000-0003-4781-7707
authors.initials: LS
authors.lastname: Manlove
authors.affiliation: Center for Immunology, University of Minnesota, Minneapolis, MN 55455; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Berquam-Vrieze
authors.affiliation: Center for Immunology, University of Minnesota, Minneapolis, MN 55455; Institute for Immunology, Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19444;
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Pauken
authors.affiliation: Puma Biotechnology, Inc., Los Angeles, CA 90024; and.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Williams
authors.affiliation: Center for Immunology, University of Minnesota, Minneapolis, MN 55455; Department of Microbiology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Marc K
authors.identifier: http://orcid.org/0000-0001-8009-7655
authors.initials: MK
authors.lastname: Jenkins
authors.affiliation: Center for Immunology, University of Minnesota, Minneapolis, MN 55455; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455; farra005@umn.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Farrar
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D003429:Cross Reactions; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology
chemical_list: C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D016044:Fusion Proteins, bcr-abl