Prevention of T cell ageing will rejuvenate anti-cancer efficacy





Graham Pawelec

Tubingen Ageing and Tumour Immunology Group, Centre for Medical Research, ZMF, University of Tubingen Medical School, Waldhornlestr. 22, D-72072 Tubingen, Germany



Tumour cells are at least initially immunogenic and can be recognised and destroyed by T lymphocytes. Tumours escape this immune destruction by a wide variety of strategies including T cell suppression. Many of the characteristics of the dysfunctional T cells found associated with tumours are shared with those found in ageing. These include shortened telomeres, increased levels of oxidative DNA damage, decreased DNA repair, decreased expression of positive and increased expression of negative costimulatory receptors, curtailed proliferative capacity, altered cytokine secretion patterns and changes in apoptosis induction (increased resistance of CD8 and increased susceptibility of CD4 T cells). It is suggested that many of these changes are caused by chronic antigenic stress (stimulation by tumour antigens in cancer patients and by persistent viruses in the elderly). These processes can be modelled in vitro in long-term clonal cultures and interventions for their prevention screened with a view to application in vivo. Additionally, extending the lifespan of tumour-specific T cells in vitro is a useful aim in itself, as these cells could be more effectively exploited for the adoptive immunotherapy of cancer if their functional integrity could be maintained over many more population doublings than presently possible. Currently promising approaches to achieve these aims include gene transfer (hTERT, proteasome ß1 or ß5 chains, HSP70 or 90, possibly DNA repair enzymes etc), manipulation of the cytokine environment, or intervening in apoptosis control pathways. Some of these interventions may find application in both ageing and cancer therapy.




Key words: cancer, immunotherapy, tumour escape, chronic antigenic stress, T cell cultures







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