title: Preventing tumor escape by targeting a post-proteasomal trimming independent epitope.
abstract: Adoptive T cell therapy (ATT) can achieve regression of large tumors in mice and humans; however, tumors frequently recur. High target peptide-major histocompatibility complex-I (pMHC) affinity and T cell receptor (TCR)-pMHC affinity are thought to be critical to preventing relapse. Here, we show that targeting two epitopes of the same antigen in the same cancer cells via monospecific T cells, which have similar pMHC and pMHC-TCR affinity, results in eradication of large, established tumors when targeting the apparently subdominant but not the dominant epitope. Only the escape but not the rejection epitope required postproteasomal trimming, which was regulated by IFN-γ, allowing IFN-γ-unresponsive cancer variants to evade. The data describe a novel immune escape mechanism and better define suitable target epitopes for ATT.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Textor
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.|Institute for Biochemistry, Charité, Campus Mitte, 10117 Berlin, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Institute for Biochemistry, Charité, Campus Mitte, 10117 Berlin, Germany.|Berlin Institute of Health, 10117 Berlin, Germany.
authors.forename: Peter-M
authors.identifier: 0000-0002-6443-4911
authors.initials: PM
authors.lastname: Kloetzel
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technical University, 81675 Munich, Germany.
authors.forename: Bianca
authors.identifier: 0000-0003-1182-4235
authors.initials: B
authors.lastname: Weißbrich
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Cynthia
authors.identifier: 0000-0002-2260-5428
authors.initials: C
authors.lastname: Perez
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Jehad
authors.initials: J
authors.lastname: Charo
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Anders
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: The Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Ton N M
authors.identifier: 0000-0003-0517-8804
authors.initials: TN
authors.lastname: Schumacher
authors.affiliation: Institute for Biochemistry, Charité, Campus Mitte, 10117 Berlin, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Keller
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technical University, 81675 Munich, Germany.
authors.forename: Dirk H
authors.identifier: 0000-0001-8713-093X
authors.initials: DH
authors.lastname: Busch
authors.affiliation: Institute for Biochemistry, Charité, Campus Mitte, 10117 Berlin, Germany.|Institute for Molecular and Clinical Immunology, Otto-von-Guericke-Universität, 39120 Magdeburg, Germany.|Friedrich Loeffler Institute of Medical Microbiology, University Medicine Greifswald, 17475 Greifswald, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Seifert
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany tblanke@mdc-berlin.de.|Berlin Institute of Health, 10117 Berlin, Germany.|Institute of Immunology, Charité, Campus Buch, 13125 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Blankenstein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000915:Antibody Affinity; D000941:Antigens / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D007931:Leucyl Aminopeptidase / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000941:Antigens; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D007931:Leucyl Aminopeptidase; C456799:puromycin-insensitive leucyl-specific aminopeptidase; D046988:Proteasome Endopeptidase Complex