Although
cancer tends to affect the elderly, most preclinical studies are carried out in young subjects. In this study, we developed a
melanoma-specific
cancer immunotherapy that shows efficacy in aged but not young hosts by mitigating age-specific
tumor-associated immune dysfunction. Both young and aged CD4(+)CD25(hi) regulatory T cells (Treg) exhibited equivalent in vitro T-cell suppression and
tumor-associated augmentation in numbers. However,
denileukin diftitox (DT)-mediated Treg depletion improved
tumor-specific immunity and was clinically effective only in young mice. DT-mediated Treg depletion significantly increased myeloid-derived suppressor cell (MDSC) numbers in aged but not young mice, and MDSC depletion improved
tumor-specific immunity and reduced
tumor growth in aged mice. Combining Treg depletion with anti-Gr-1 antibody was immunologically and clinically more efficacious than anti-Gr-1 antibody alone in aged B16-bearing mice, similar to Treg depletion alone in young mice. In contrast, DT increased MDSCs in young and aged mice following MC-38
tumor challenge, although effects were greater in aged mice. Anti-Gr-1 boosted DT effects in young but not aged mice. Aged antitumor immune effector cells are therefore competent to combat
tumor when underlying
tumor-associated immune dysfunction is appropriately mitigated, but this dysfunction varies with
tumor, thus also varying responses to
immunotherapy. By tailoring
immunotherapy to account for age-related
tumor-associated immune dysfunctions,
cancer immunotherapy for aged patients with specific
tumors can be remarkably improved.