There is no question that the prevalence of neoplastic disease increases with age. There is a concomitant decrease in immune responses, particularly in T cell response, although no definitive data support a causal relationship. However, with the increased interest in adoptive immunotherapy (i.e., LAK cells, TILs) and biologic response modifiers (e.g., interferon [IFN]) for cancer treatment, the ability of the immune response of elderly subjects to respond to immunotherapy needs to be carefully examined. In vivo data from the applicant's laboratory, using two different tumor models, indicate that, while immunotherapy of young mice with IFN results in increased survival, similar therapy in aged mice has no effect on tumor growth. Furthermore, these studies indicate that, in young mice, the anti-tumor effect of IFN is dependent upon the presence of asialoGM1+ cells (presumably NK cells), whose activity is regulated by CD4+ and CD8+ T cells. In addition, the applicant's in vitro studies appear to indicate that NK cells of aged mice demonstrate a decreased ability to be activated by IFN. It is therefore hypothesized that: the lack of effectiveness of immunotherapy in aged mice is due to a decrease in the expression of enhanced NK activity, either directly or indirectly. The proposed studies will use IFN as a model to define the changes in the aged cancer host that are responsible for the lack of response to immunotherapy. Specifically, the applicant will attempt to: 1) determine if NK cells of aged mice lack the capacity for increased activity after IFN treatment due to an inherent cellular defect; and 2) assess if dysregulation of CD4+ and CD8+ T cells in aged mice influences NK activity.
| Plett, A; Murasko, D M (2000) Genetic differences in the age-associated decrease in inducibility of natural killer cells by interferon-alpha/beta. Mech Ageing Dev 112:197-215 |
| Plett, P A; Gardner, E M; Murasko, D M (2000) Age-related changes in interferon-alpha/beta receptor expression, binding, and induction of apoptosis in natural killer cells from C57BL/6 mice. Mech Ageing Dev 118:129-44 |
