Manipulation of dendritic cells for cancer immunotherapy circumventing VEGF inhibition

Abstract

The American Cancer Society predicts 1,638,910 new cancer cases during 2012. 577,190 of these cases will result in death, a rate of 35.2%. The high death rate coupled with the adverse side effects and reduced quality of life that result from traditional cancer therapies highlight the importance of searching for more effective and tolerable treatments. Under most conditions, foreign invaders are recognized by antigen presenting cells (APCs) including dendritic cells (DCs) that initiate an immune response to remove the threat. However, tumor cells are not foreign invaders, but rather arise from host cells. Tumors are able to use their origin as a means to evade an immune response by taking advantage of the immune system's self-tolerance. Other escape mechanisms include release of inhibitory factors by tumor cells such as vascular endothelial growth factor (VEGF). VEGF affects the activation of NF-kB signaling required for the maturation of DCs, rendering DCs unable to stimulate cytotoxic T cells to target and kill tumor cells. Despite these complications, DCs are remain the most potent APC and are uniquely capable of promoting T cell activation and differentiation into effector cells. These qualities make DCs ideal candidates for cancer immunotherapy in clinical studies. Current DC-based cancer immunotherapy loading ex vivo or in vitro generated DCs with tumor antigens from a various sources. Ex vivo or in vitro manipulation enables researchers to control the quality and maturation of DCs to help circumvent the effects of VEGF, and thereby significantly increase the ability of DCs to present and activate T cells. This review aims to explore the mechanism by which VEGF inhibits natural DC function to better understand the necessary adjustments to make in ex vivo/in vitro manipulation. Additionally, we will present various methods of DC therapy as well as the results of successful clinical trials in order to suggest which of these methods may be the most effective and the focus of future studies.