title: Engineering anticancer T cells for extended functional longevity.
abstract: Like other somatic cells, human T lymphocytes have a finite replicative capacity in vitro, and, by implication and consistent with the limited data available, in vivo as well. An accumulation of dysfunctional T cells may be detrimental under conditions of chronic antigenic stress (chronic infection, cancer, autoimmunity). Using T cells from young donors to model the process of T cell clonal expansion in vitro under these conditions reveals age-associated increasing levels of oxidative DNA damage and microsatellite instability (MSI), coupled with decreasing DNA repair capacity, telomerase induction and telomere length, decreased levels of expression of the T cell costimulator CD28 and consequently reduced secretion of the T cell growth factor interleukin-2 (IL-2). However, data from similar experiments using T cell clones (TCCs) derived from extremely healthy very elderly donors ("successfully aged") indicate that DNA repair is better maintained, MSI less prevalent, and (already short) telomere lengths are maintained. Nonetheless, oxidative DNA damage is seen to the same extent, and clonal longevity is also similar in these clones. DNA damage levels are reduced by culture in 5% oxygen, but longevity is not improved. This may be because of the requirement for intermittent reactivation via receptor pathways dependent on free radical production in T cells. These recent findings from our international immunosenescence research consortium suggest that strategies other than telomere maintenance, better protection against free radicals, or improved DNA repair will be required for functional longevity extension of human TCCs. To obtain sufficient cells for adoptive immunotherapy of cancer, alternative avenues need exploration; currently, these include enforced expression of certain heat shock proteins and proteasome components, and interference with the expression of negative regulatory receptors expressed by T cells.
authors.affiliation: Center for Medical Research, ZMF, University of Tübingen Medical School, Waldhörnlestrasse 22, D-72072 Tuebingen, Germany. graham.pawelec@uni-tuebingen.de
authors.forename: Graham
authors.initials: G
authors.lastname: Pawelec
authors.forename: Erminia
authors.initials: E
authors.lastname: Mariani
authors.forename: Julie
authors.initials: J
authors.lastname: McLeod
authors.forename: Arie
authors.initials: A
authors.lastname: Ben-Yehuda
authors.forename: Tamas
authors.initials: T
authors.lastname: Fulop
authors.forename: Martin
authors.initials: M
authors.lastname: Aringer
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Barnett
mesh_terms: D000941:Antigens / Q000378:metabolism; D018106:CD28 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D005609:Free Radicals; D006801:Humans; D007167:Immunotherapy; D008024:Ligands; D008136:Longevity; D018895:Microsatellite Repeats; D009097:Multienzyme Complexes / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000941:Antigens; D018106:CD28 Antigens; D005609:Free Radicals; D008024:Ligands; D009097:Multienzyme Complexes; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D019098:Telomerase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen