Impaired Dendritic Cell Migration and T cell Stimulation in Aging Lead to Defective Dendritic Cell‐Mediated Antitumor Immunity

Abstract

We recently reported that bone marrow‐derived dendritic cells (DCs) from old C57BL/6 mice are less effective than their young counterpart in inducing the regression of B16‐OVA melanomas. To examine the underlying mechanisms, we investigated the effect of aging on DC tumor antigen presentation and migration. Although aging does not affect the ability of DCs to present OVA peptide (257–264), DCs from aged (18–20 months) mice are less efficient than those from young (3–6 months) mice in stimulating MHC class I OVA‐specific T cells in vitro (p<0.0025). Phenotypic analysis revealed a selective decrease in DC‐specific/intracellular adhesion molecule type 3‐grabbing, nonintegrin (DC‐SIGN) level in aged DCs. Importantly, vaccination of young mice using old OVA‐peptide(257–264) pulsed DCs resulted in impaired activation of OVA‐specific CD8+ splenic T cells in vivo (p<0.025). These splenic T cells from aged animals were able to differentiateinto IFN‐γ‐producing and cytotoxic effectors, but to a significantly less extent than those vaccinated with young OVA PP‐DCs. A decrease influx of CD8+ T cells within the tumor was also observed seven days after old DC injection. Finally, adoptive transfer experiments showed defective in vivo DC trafficking in aging, with half as many aged DCs migrated to the regional lymph nodes (p<0.025). This correlates with reduced CCR7 gene expression, impaired in vitro migration of aged DCs in response to CCL21, and defective CCR7 signaling in aged DCs. Taken together, our findings suggest that defective DC migration and T cell stimulation contribute to the observed impaired DC tumor immunotherapeutic response in aging.This work id supported by the NIH (1RO1AG020628‐01A2; 3RO1 AR42525) (RY), the Ann Arbor VA Health System (VA Merit Review) (RY), and by the NIH‐NIA (AG024824, University of Michigan OAIC Pepper Center) (AG).