Engineering anticancer T cells for extended functional longevity

Annals of the New York Academy of Sciences
G PawelecYvonne Barnett

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 ...Continue Reading

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Citations

Apr 9, 2008·Rejuvenation Research·Marco MalavoltaEugenio Mocchegiani
Aug 10, 2010·The Cancer Journal·Cassian Yee
Mar 1, 2006·Immunity & Ageing : I & a·Sonya VastoGraham Pawelec
Mar 23, 2007·Immunity & Ageing : I & a·Sonya VastoGraham Pawelec
May 11, 2005·Immunological Reviews·Rita B EffrosJanice Man

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