title: Hepatitis C virus-cross-reactive TCR gene-modified T cells: a model for immunotherapy against diseases with genomic instability.
abstract: A major obstacle hindering the development of effective immunity against viral infections, their associated disease, and certain cancers is their inherent genomic instability. Accumulation of mutations can alter processing and presentation of antigens recognized by antibodies and T cells that can lead to immune escape variants. Use of an agent that can intrinsically combat rapidly mutating viral or cancer-associated antigens would be quite advantageous in developing effective immunity against such disease. We propose that T cells harboring cross-reactive TCRs could serve as a therapeutic agent in these instances. With the use of hepatitis C virus, known for its genomic instability as a model for mutated antigen recognition, we demonstrate cross-reactivity against immunogenic and mutagenic nonstructural protein 3:1406-1415 and nonstructural protein 3:1073-1081 epitopes in PBL-derived, TCR-gene-modified T cells. These single TCR-engineered T cells can CD8-independently recognize naturally occurring and epidemiologically relevant mutant variants. TCR-peptide MHC modeling data allow us to rationalize how TCR structural properties accommodate recognition of certain mutated epitopes and how these substitutions impact the requirement of CD8 affinity enhancement for recognition. A better understanding of such TCRs' promiscuous behavior may allow for exploitation of these properties to develop novel, adoptive T cell-based therapies for viral infections and cancers exhibiting similar genomic instability.
authors.affiliation: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA; tspear@luc.edu.
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Spear
authors.affiliation: Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA;
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Riley
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois, USA; Department of Biology, Northeastern Illinois University, Chicago, Illinois, USA;
authors.forename: Gretchen E
authors.initials: GE
authors.lastname: Lyons
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois, USA; Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA;
authors.forename: Glenda G
authors.initials: GG
authors.lastname: Callender
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois, USA;
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Roszkowski
authors.affiliation: Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Flow Cytometry Core Facility, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA;
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Simms
authors.affiliation: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA;
authors.forename: Gina M
authors.initials: GM
authors.lastname: Scurti
authors.affiliation: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA;
authors.forename: Kendra C
authors.initials: KC
authors.lastname: Foley
authors.affiliation: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA;
authors.forename: David C
authors.initials: DC
authors.lastname: Murray
authors.affiliation: Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA;
authors.forename: Lance M
authors.initials: LM
authors.lastname: Hellman
authors.affiliation: Division of Gastroenterology and Hepatology, Hepatitis C Center, and Department of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado, USA; and.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: McMahan
authors.affiliation: Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois, USA;
authors.forename: Makio
authors.initials: M
authors.lastname: Iwashima
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.affiliation: Division of Gastroenterology and Hepatology, Hepatitis C Center, and Department of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado, USA; and.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Rosen
authors.affiliation: Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA;
authors.forename: Brian M
authors.initials: BM
authors.lastname: Baker
authors.affiliation: Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA; Department of Surgery, University of Chicago, Chicago, Illinois, USA;
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
mesh_terms: D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D042822:Genomic Instability; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000209:etiology / Q000517:prevention & control*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell
keywords: altered peptide ligands; computational modeling; peptide-MHC