Metabolic influences that regulate dendritic cell function in tumors

Dendritic cells (DC) are critical regulators of both activation and tolerance in the adaptive immune response. The dual nature of DC immunoregulatory function depends on their differentiation and activation status. DC found within the tumor microenvironment (TME) and tumor-draining lymph node often exist in an inactive state, which is thought to limit the adaptive immune response elicited by the growing tumor. The major determinants of DC activation and the functional alterations in DC that result from integrating exogenous stimuli have been well investigated. Extensive efforts have been made to elucidate how the TME contributes to the inactivated/dysfunctional phenotype of tumor-associated DC (TADC). Although performed predominantly on in vitro DC cultures, recent evidence indicates that DC undergo required, coordinated alterations in their metabolism upon activation, and dysregulated metabolism in TADC is associated with their reduced immunostimulatory capacity. In this review, we will focus on the role of glycolysis and fatty acid metabolism in DC activation and function and discuss how these metabolic pathways may be regulated in TADC. Further, we consider the need for developing novel experimental approaches to assess metabolic choices in vivo, and the necessity for integrating metabolic regulation into the optimized development of DC for tumor vaccines and immunotherapy for cancer.