title: Target Density, Not Affinity or Avidity of Antigen Recognition, Determines Adoptive T Cell Therapy Outcomes in a Mouse Lymphoma Model.
abstract: Adoptive T cell therapy (ACT) with antitumor CTL is a promising and tailored treatment against cancer. We investigated the role played by the affinity and avidity of the interaction between the tumor and the CTL on the outcome of ACT against a mouse non-Hodgkin B cell lymphoma that expresses OVA as a model neoantigen. ACT was assessed under conditions where antitumor CTL expressed TCR of varying affinity for OVA. We also assessed conditions where the avidity of Ag recognition varied because the lymphoma cells expressed high or low levels of OVA. Efficient eradication of small tumor burdens was achieved by high- or low-affinity CTL. Tumors expressing low levels of OVA could also be eliminated. However, ACT against large tumor burdens was unsuccessful, accompanied by CTL deletion and functional impairment. This negative outcome was not prevented by lowering the affinity of the CTL or the expression of OVA in the lymphoma. Thus, tumor burden, rather than CTL affinity or avidity, appears to be the main determinant of ACT outcomes in our lymphoma model. Insofar as our results can be extrapolated to the clinical setting, they imply that the range of CTL and tumor-associated Ag combinations that may be effectively harnessed in ACT against lymphoma may be wider than generally assumed. CTL expressing low-affinity TCR may be effective against lymphoma, and lowly expressed tumor-associated Ag should be considered as potential targets, but tumor reduction should always be implemented before infusion of the CTL.
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Gabriela
authors.identifier: 0000-0002-4954-0337
authors.initials: G
authors.lastname: Segal
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Sandro
authors.initials: S
authors.lastname: Prato
authors.affiliation: Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland; Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, 1011 Lausanne, Switzerland; and.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Zehn
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3010, Australia jmintern@unimelb.edu.au j.villadangos@unimelb.edu.au.
authors.forename: Justine D
authors.identifier: 0000-0002-3797-8577
authors.initials: JD
authors.lastname: Mintern
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3010, Australia jmintern@unimelb.edu.au j.villadangos@unimelb.edu.au.
authors.forename: Jose A
authors.identifier: 0000-0001-6771-8891
authors.initials: JA
authors.lastname: Villadangos
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation
chemical_list: D000941:Antigens; D019496:Cancer Vaccines; D011948:Receptors, Antigen, T-Cell