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Decreases in macrophage mediated antitumor activity with aging
P K Wallace1, T K Eisenstein, J J Meissler
1Department of Microbiology and Immunology, Medical College of Pennsylvania, Philadelphia 19129, USA.
Abstract:
We have demonstrated that immunotherapy of young (6-10 weeks old), and aged, (greater than 24 months old), tumor bearing mice with biological response modifiers enhanced survival and inhibited tumor growth, while treatment of aged mice had little or no effect. We hypothesized that the antitumor activity in young mice was principally mediated by activated macrophages (M phi) and predicted that the change in aged mice was caused by an intrinsic M phi defect which develops with advancing age. To directly test our hypothesis, we examined the antitumor activity of resident peritoneal M phi, purified and activated in vitro with IFN gamma plus LPS. Paralleling the results seen in vivo, M phi from aged mice exhibited reduced antitumor activity in comparison with M phi from younger mice. Moreover, there was reduced capacity of in vitro activated M phi from aged mice to produce TNF, IL-1 and nitric oxide, which are critical monokines and effector molecules that have been established to either directly inhibit tumor growth or cause tumor cell destruction. These studies establish that peritoneal M phi from aged mice have an intrinsic defect which prevents them from fully expressing their antitumor potential.
Insights
Immunotherapy effectively treats tumors in young mice but not aged mice, suggesting age-related defects in macrophages (M phi). Aged M phi show reduced antitumor activity and lower production of key molecules like TNF and IL-1.
Area of Science:
- Immunology
- Aging Research
- Cancer Biology
Background:
- Immunotherapy using biological response modifiers shows differential efficacy in young versus aged tumor-bearing mice.
- Enhanced survival and tumor growth inhibition were observed in young mice, but not in aged mice.
Purpose of the Study:
- To investigate the hypothesis that age-associated defects in macrophages (M phi) contribute to the reduced efficacy of immunotherapy in aged mice.
- To directly assess the antitumor activity and cytokine production of peritoneal M phi from young and aged mice.
Main Methods:
- Peritoneal M phi were isolated from young and aged mice.
- M phi were activated in vitro using interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS).
- Antitumor activity, tumor necrosis factor (TNF), interleukin-1 (IL-1), and nitric oxide production were measured.
Main Results:
- M phi from aged mice exhibited significantly reduced in vitro antitumor activity compared to M phi from young mice.
- Activated M phi from aged mice showed diminished capacity to produce TNF, IL-1, and nitric oxide.
- These findings correlate with the in vivo observations of immunotherapy efficacy.
Conclusions:
- Peritoneal macrophages from aged mice possess an intrinsic defect that impairs their antitumor potential.
- This age-related M phi defect is a key factor limiting the effectiveness of immunotherapy in older individuals.
- Restoring M phi function may be a therapeutic strategy to improve cancer treatment outcomes in the elderly.