Signaling of tumor-induced immunosuppression of dendritic cells

Dendritic cells (DCs) are professional antigen-presenting cells that regulate the immune system. In cancers, they uptake tumor-associated antigens, deliver them to T cells, and induce tumor-specific T cell responses. However, tumor cells develop mechanisms to evade the immune system, partly by impairing DC differentiation and function. Functionally deficient DCs may associate with acquisition of tolerogenic/immunosuppressive activities that actively block the development of antitumor immunity, and there is strong evidence supporting the presence of regulatory DCs in different DC subsets. Mechanistic studies reveal that intracellular signaling pathways, such as MAP kinases (MAPKs), JAK/STAT3, PI3 K/Akt, and NF-κB, which are critical to the regulation of DC differentiation, survival, and activity, are found to be hyperactivated both in tumor cells and in DCs in malignancies. The constitutive activation of these pathways in cancer cells leads to tumor cell secretion of cytokines that activate intracellular signaling pathways, particularly p38 MAPKs, in DCs or their progenitor cells and impair DC differentiation and function. In this chapter, we will discuss the dysfunction of DCs and the presence of regulatory DCs in cancer settings. We will focus on the signaling pathways that mediate DC dysfunction, particularly p38 MAPKs, in negatively regulating DC differentiation and function in cancers.