Impaired Dendritic Cell Function in Aging Leads to Defective Antitumor Immunity

Abstract

We recently reported that bone marrow-derived dendritic cells (DC) from aged miced are less effective than their young counterparts in inducing the regression of B16-ovalbumin (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)(258)(259)(260)(261)(262)(263)(264) , DCs from aged mice are less efficient than those from young mice in stimulating OVA-specific T cells in vitro. Phenotypic analysis revealed a selective decrease in DC-specific/intracellular adhesion molecule type-3-grabbing nonintegrin (DC-SIGN) level in aged DCs. Adoptive transfer experiments showed defective in vivo DC trafficking in aging. This correlates with impaired in vitro migration and defective CCR7 signaling in response to CCL21 in aged DCs. Interestingly, vaccination of young mice using old OVA peptide (257-264) -pulsed DCs (OVA PP-DC) resulted in impaired activation of OVA-specific CD8 + T cells in vivo. Effector functions of these T cells, as determined by IFN-; production and cytotoxic activity, were similar to those obtained from mice vaccinated with young OVA PP-DCs. A decreased influx of intratumor CD8 + T cells was also observed. Importantly, although defective in vivo migration could be restored by increasing the number of old DCs injected, the aging defect in DC tumor surveillance and OVA-specific CD8 + T-cell induction remained. Taken together, our findings suggest that defective T-cell stimulation contributes to the observed impaired DC tumor immunotherapeutic response in aging. [Cancer Res 2008;68(15):6341-9]

The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3+ lymphocyte-primed multipotent precursors

“…[39][40][41][42] Here, we rejuvenated the differentiation of aged DC via pharmacological inhibition of the non-canonical Wnt pathway, providing a new strategy for the treatment of DC aging-related immune disorders.…”

Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL‐17 producing T cells

“…Aging brings about changes in the immune system, the best-described of which include loss of functions, such as reduced priming of naïve T cells (Bansal-Pakala & Croft, 2002) and reduced activation properties of dendritic cells (Grolleau-Julius et al, 2008). Nonetheless, at the same time, other immune functions become exaggerated, such as increased suppression by myeloid-derived suppressor cells (Grizzle et al, 2007) or dysfunction best evidenced by general increases in systemic inflammation (Sergio, 2008).…”

What can proteomics teach us about bone marrow aging?

“…The pivotal humoral and cellular immunity are defective owing to both the declined diversity of B-cell receptor/T-cell receptor and reduced size of B-/T-cell compartments [25,26]. In addition, aging affects the function of dendritic cells (DCs), which are linked to the lowered antitumor capacity in the elderly [27]. Previous studies ascribed the reduced immunocompetence to the defective differentiation potential of HSCs, and the intrinsic and microenvironmental changes of immune cells induced by aging [25,[28][29][30], although the underlying mechanism is largely unknown.…”