Tumor-Altered Dendritic Cell Function: Implications for Anti-Tumor Immunity

Abstract

Dendritic cells (DC) are key regulators of both innate and adaptive immunity, and the array of immunoregulatory functions exhibited by these cells is dictated by their differentiation, maturation, and activation status. Although a major role for these cells in the induction of immunity to pathogens has long been appreciated, data accumulated over the last several years has demonstrated that DC are also critical regulators of anti-tumor immune responses. However, despite the potential for stimulation of robust anti-tumor immunity by DC, tumor-altered DC function has been observed in many cancer patients and tumor-bearing animals and is often associated with tumor immune escape. Such dysfunction has significant implications for both the induction of natural anti-tumor immune responses as well as the efficacy of immunotherapeutic strategies that target endogenous DC in situ or that employ exogenous DC as part of anti-cancer immunization maneuvers. In this review, the major types of tumor-altered DC function will be described, with emphasis on recent insights into the mechanistic bases for the inhibition of DC differentiation from hematopoietic precursors, the altered programing of DC precursors to differentiate into myeloid-derived suppressor cells or tumor-associated macrophages, the suppression of DC maturation and activation, and the induction of immunoregulatory DC by tumors, tumor-derived factors, and tumor-associated cells within the milieu of the tumor microenvironment. The impact of these tumor-altered cells on the quality of the overall anti-tumor immune response will also be discussed. Finally, this review will also highlight questions concerning tumor-altered DC function that remain unanswered, and it will address factors that have limited advances in the study of this phenomenon in order to focus future research efforts in the field on identifying strategies for interfering with tumor-associated DC dysfunction and improving DC-mediated anti-tumor immunity.

Norm- and hypo-fractionated radiotherapy is capable of activating human dendritic cells

“…Their maturation is pivotal in this context. Only entirely matured DC (mDC) with immunostimulatory phenotypes are able to induce anti-tumor immune responses, whereas iDC can provoke tumor progression (Hargadon, 2013). Thus, we co-incubated iDC with SN of the differently irradiated colorectal tumor cells and analyzed afterwards their maturation state to determine irradiation protocols that stimulate DC maturation most effectively.…”

Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells

“…These TiDCs acquire TAAs; however, they are unable to present them to and properly activate CTLs. This dysfunction is due to immunosuppressive factors present in the tumor microenvironment (28). Several strategies aimed at improving the function of TiDCs have been developed.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…M2 macrophages contribute to the formation of an immunosuppressed microenvironment. TAMs often show a M2 phenotype [51] and are characterized by the secretion of VEGF, HIF, TGFβ, IL-10, Arginase I and reactive oxygen species (ROS) [52], as well as various chemokines such as CCL2, CCL5 (RANTES), CXCL9, CXCL10, and CXCL16 [53]. TAMs contribute to tumor growth and progression through extracellular matrix remodeling, promotion of tumor cell invasion and metastasis, angiogenesis, lymphangiogenesis and immune suppression [6].…”

“…IDO is also produced by MDSCs, regulatory dendritic cells and TAMs [6,52,125,126]. Silencing of IDO within the tumor using Salmonella typhimurium as a tumor-homing vector to deliver a short-hairpin RNA targeting IDO, allowed tumor infiltration of activated ROS-producing neutrophils and consequent tumor cell death [127].…”