Immune responses wane during aging, posing challenges to the potential effectiveness of cancer immunotherapies. We previously demonstrated that in the context of a promising immunotherapeutic, OX40 agonist (αOX40), older animals exhibited impaired anti-tumor immune responses and diminished CD4 T cell effector differentiation. In this study, we hypothesized that tumor immune responses could be maintained during aging through caloric restriction (CR) or dietary supplementation with resveratrol (RES), a CR mimetic. Mice were placed on either a calorically restricted diet or a RES-formulated diet starting between 4 and 6 months of age and continued until mice reached 12 months of age. Tumor immune responses were assessed after challenging with either sarcoma or breast tumor cells followed by αOX40 treatment. Our results show that CR, but not RES, maintained OX40-mediated anti-tumor immunity. In addition, CR fully sustained antigen-specific CD4 T cell priming in aged hosts (12 months old), whereas tumor-specific CD8 T cell priming was not fully maintained compared to young reference animals (2 months old). Thus, CR appears to maintain immunological fitness of the CD4 T cell priming environment during aging, which is critical for optimal OX40-mediated responses.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-014-1542-y) contains supplementary material, which is available to authorized users.

Decline in CD4 T cell immune responses is associated with aging. Although a number of immunological defects have been identified in elderly mice (>18 months old), a key early-onset immune defect at middle age could be a driver or contributor to defective CD4 T cell responses. Our studies demonstrate that age-related alterations in DC subsets within the priming environment of middle-aged mice (12 months old) correlate with and can directly contribute to decreases in antigen-specific CD4 T cell Th1 differentiation, which measured by T-bet and IFN-γ expression, was decreased significantly in T cells following VSV infection or s.c. immunization with a protein antigen in the context of immune stimulation via OX40. The deficient Th1 phenotype, observed following protein antigen challenge, was found to be the result of an age-related decrease in an inflammatory DC subset (CD11b+ Gr-1/Ly6C+) in the dLN that corresponded with T cell dysfunction. In the virus model, we observed significant changes in two DC subsets: mDCs and pDCs. Thus, different, early age-related changes in the DC profile in the priming environment can significantly contribute to impaired Th1 differentiation, depending on the type of immunological challenge.

Immune responses progressively wane during aging, posing significant challenges to the protection and treatment of cancer. We previously demonstrated that in the context of OX40 costimulation older animals exhibited impaired anti-tumor immune responses and diminished CD4 T cell effector differentiation. We hypothesized that anti-tumor immune responses could be maintained during aging through caloric restriction (CR) or dietary supplementation with resveratrol (RES), a CR mimetic. Mice were placed on either a restricted diet or a RES-formulated diet starting between 4 and 6 months of age and continued until mice reached 12 months of age. Tumor immune responses were assessed by challenging with either sarcoma or breast tumor cells followed by agonist OX40 treatment. Our results show CR, but not RES, maintained OX40-mediated anti-tumor immunity, during aging. In addition, CR maintained tumor-specific CD4 T cell activation in aged mice. This observed effect of CR on T cell activation, lead to an assessment of DCs. We found that the accumulation of an inflammatory DC subset (CD11c+CD11b+Ly6C+), critical for the activation of CD4 T cells, was significantly decreased in the LNs of older control mice compared to young mice. In contrast, CR aged mice had more inflammatory DCs in the priming LNs compared to aged controls. Thus, CR appears to maintain immunological fitness of a DC subset during aging that is critical for antigen-specific CD4 T cell activation and tumor immunity.