Dendritic cell-targeted approaches to modulate immune dysfunction in the tumor microenvironment

Abstract

There has been enormous progress this past decade in the understanding of the biology of dendritic cells (DCs) along with increasing attention for the development of novel dendritic cell (DC)-based cancer therapies. However, the clinical impact of DC-based vaccines remains to be established. This limited success could be explained by suboptimal conditions for generating potent immunostimulatory DCs as well as immune suppression mediated by the tumor microenvironment (TME). Therefore, strategies that optimize the potency of DC vaccines along with newly described therapies that target the TME in order to overcome immune dysfunction may provide durable tumor-specific immunity. These novel interventions hold the most promise for successful cancer immunotherapies.

Keywords: cancer; dendritic cells; immune checkpoints; immunotherapy; tumor microenvironment.

Figure 1

Dysregulation of dendritic cell-mediated anti-tumor immune responses by tumor microenvironment. Effector T cells can recognize and kill tumor targets after activation by immunogenic dendritic cells. However, a number of soluble mediators, including TGFβ, IL-10, and alarmins, that are secreted by immuno-suppressive cells such as Treg cells, MDSCs, and tumor cells can dysregulate dendritic cells function and limit T-cell effector functions. (A) Exposure to pathogens induces the maturation of immunogenic dendritic cells that secrete large amounts of IL-12 upon activation. IL-12 mediates enhancement of the cytotoxic activity of NK cells and CD8⁺ cytotoxic T lymphocytes, is involved in the differentiation of naive T cells into T_H1 cells, and stimulates the production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) from T and NK cells cells. (B) In the tumor microenvironment, development of detrimental/suboptimal T_H2 cells is induced by alarmins such as TSLP, EDN, and MMP-2 through mechanisms depending on inflammatory DCs. (C) Immuno-suppressive cytokines such as IL-10 and TGF-β are responsible for the induction of immature/tolerogenic/immuno-suppressive DCs able to promote the accumulation of regulatory T cells. Tregs play a crucial role in maintaining a suppressive environment and inhibiting anti-tumor responses.

Figure 2

Anti-tumor immunotherapies. (A) There is currently no consensus on the optimal strategy to generate DCs for immunotherapeutic use regarding DC subsets, maturation stimuli, and methods to load antigens. (B) Therapies aiming at reprograming the immuno-suppressive TME are very promising, including blockade of immune checkpoints as well as inhibitors of alarmins and immuno- suppressive cytokines. (C) Strategies targeting DCs in vivo include administration of activation stimuli (Poly I:C, CD40L, Flt3L), in vivo delivery of tumor antigens, and administration of tumor antigens coupled with antibody against DC surface receptors.