Effective age-specific tumor immunotherapy for B16 melanoma by targeting age-related immune dysfunction (46.42)

Abstract

Abstract Age is the biggest risk factor for cancer but most studies are in young hosts. We mitigated age-specific tumor-related immune dysfunction to develop immunotherapy for B16 melanoma effective in aged hosts. Young and aged CD4+CD25hi regulatory T cells (Tregs) had similar in vitro function and in vivo tumor-associated increases, but denileukin diftitox (DT)-mediated Treg depletion improved tumor-specific immunity and was clinically effective only in young mice. Aged mice had more basal and tumor-related myeloid derived suppressor cells (MDSC). Depleting MDSC with anti-Gr-1 Ab improved tumor-specific immunity and clinical response better in aged versus young mice. Treg depletion significantly increased MDSC in aged but not young mice, suggesting age-related Treg control of MDSC. In vitro, Treg from aged tumor bearing mice suppressed GM-CSF-induced bone marrow MDSC differentiation. Treg depletion + anti-Gr-1 Ab was more efficacious than anti-Gr-1 alone in aged B16-bearing mice but was no better than Treg depletion alone in young mice. In MC-38 colon cancer, DT and anti-Gr-1 Ab effects were similar in young and aged hosts. Thus aged anti-tumor immune effector cells are competent to combat tumor when tumor-associated immune dysfunction is appropriately mitigated, and age-related immune dysfunction is tumor-dependent. Tailoring immunotherapy to counter age-related, tumor-associated immune dysfunctions remarkably improves cancer immunotherapy for aged patients with specific tumors.