Dendritic cells in cancer: the role revisited

Abstract

Dendritic cells (DCs) with their potent antigen presenting ability are long considered as critical factor in antitumor immunity. Despite high potential in promoting antitumor responses, tumor-associated DCs are largely defective in their functional activity and can contribute to immune suppression in cancer. In recent years existence of immune suppressive regulatory DCs in tumor microenvironment was described. Monocytic myeloid derived suppressor cells (M-MDSCs) can contribute to the pool of tumor associated DCs by differentiating to inflammatory DCs (inf-DCs), which appear to have specific phenotype and is critical component of antitumor response. Here we examine the role of inf-DCs along with other DC subsets in the regulation of immune responses in cancer. These novel data expand our view on the role of DCs in cancer and may provide new targets for immunotherapy.

Figure 1. DC subsets in tumor micoenvironment

(A) DCs arise from macrophage/DC progenitors (MDPs) in the bone marrow. MDPs give rise to the common monocyte progenitors (cMOPs) and to the common DC precursors CDPs. CDPs further differentiate into plasmacytoid DCs (pDCs) and pre-cDCs. pDCs terminally differentiated in the bone marrow, pre-cDCs become fully differentiated in conventional DCs (cDCs) in periphery. (B) In lymphoid and non-lymphoid tissues in tumor-free hosts, cDCs differentiate into CD11b⁺, CD103⁺ and CD8⁺ subsets. cMOPs give rise to monocyte, which can differentiate in macrophages and small number of DCs. (C) In tumor microenvironment (TME), pre-DC differentiate to two rare populations of DCs: CD11b+DCs (DC1) and CD103+DCs (DC2). Monocytes reach the TME and differentiate to macrophages and inflammatory DCs (Inf-DCs). pDCs are also found infiltrated in the in TME. (D) DC2s and inf-DCs migrate to dLNs in a CCR7 dependent manner and cross-present tumor antigens to CD8 T cells, starting antitumor responses.

Figure 2. Mechanisms of DC dysfunction in cancer

(A) Hypoxia, adenosine, lactic acid, low pH impair the ability of DCs to stimulate T cell responses. (B) IL-10 induces the differentiation of tolerogenic DCs, characterized by a low expression of costimulatory and MHC molecules, and high production of IL-10. (C) IL-10 produced by TAM inhibits the production of IL-12 by CD103⁺DCs, resulting in an impaired T cell activation. (D) The expression of PD-L1 on CD103⁺DCs in TME contributes to their dysfunction. (E) Tumor derived factors drive the differentiation of immunosuppressive inf-DC. They produce tumor promoting IL-6 and immunosuppressive galectin-1. (F) Abnormal accumulation of lipids in DCs impairs their ability to cross-present tumor antigens. (G) pDCs produce low amount of type I IFN but show higher expression of OX40L and ICOSL. The expression of these markers is associated with the production of IL-5, IL-10, and IL-13 by T cells. (H) IDO producing pDCs induce the differentiation of Treg cells in TME.