Age effects on tumor B7-H1 and related immune therapies in an aggressive model of ovarian cancer.

Abstract

Abstract Age is the greatest cancer risk factor, but contributions of aging to tumor intrinsic properties and immunotherapy responses are poorly understood as most preclinical studies are in young hosts. We assessed age effects on tumor properties, progression, immunity and response to immunotherapies in an aggressive ID8 ovarian cancer line (ID8agg) that is poorly immunogenic and fatal in ~5 weeks. Young (3 mos) and aged (24 mos) BL6 females were injected intraperitoneally with 4×106 syngeneic ID8agg cells. In young mice, ID8agg ascites had more regulatory T cells (Tregs) and myeloid suppressor cells (MDSCs). Young mice gained 30% weight from ascites ~30 days after ID8agg challenge and formed 1–2 large, discrete peritoneal tumor masses. Aged mice tended to lose weight although ascites volumes were comparable to young, suggesting cachexia, and formed multiple small peritoneal nodules. Aged ascites had more tumor cells, Tregs, monocytic MDSCs and PD-1+ T cells versus young. Strikingly, tumor cells and MDSCs in aged ascites upregulated the immune checkpoint molecule B7-H1 greater than in young ascites. The combination of depleting Tregs and MDSCs with denileukin diftitox (DD), an FDA-approved IL-2/diphtheria toxin + αGr-1 temporarily slowed tumor progression in aged mice with increased IFNγ+ CD8 T cells, consistent with our prior B16 data. Treg depletion with either DD or αCD25 alone, or plus αCTLA4 did not significantly prevent ID8agg progression in young or aged mice. In young hosts, αB7-H1 slowed tumor growth and increased survival, with both clinical outcomes potentiated by adding αCTLA4. αCTLA4 + αB7-H1 effects in aged hosts are under study. Thus, we identified major age effects on tumor progression, and immune and immunotherapy responses.