In this review, we will discuss the DC subtypes, functional properties and interaction with other immune cells in the TME and highlight established and developing therapies that target DC. A deeper understanding of how these DC functions are modulated and regulated by the TME will lead to the development of improved DC-targeted therapies. DC function is determined by influences from surrounding cells and the microenvironment, including the TME which adversely impacts DC intratumoral entry and function, and consequently an effective anti-tumor immune response. DCs have a unique ability to migrate to the draining lymph nodes to initiate T cell activation by presenting antigens and by providing immunomodulatory signals through cell-to-cell contacts and cytokines.Ī major issue in the development of these therapies is the impairment of DC functions in the tumor microenvironment (TME). Dendritic cells (DCs) are the most representative professional APCs. APCs have abilities to capture, process, and present non-self-antigens to T cells, and express major histocompatibility complex (MHC) I and II as well as key costimulatory molecules for T cell engagement. A common and important component required for the success of each of these strategies is the presentation of tumor antigens to T cells by professional antigen-presenting cells (APCs). These therapies enhance the tumor antigen-specific T cell response and in combination with ICI can potentially improve response rates with enhanced migration of T cells into the tumor site and epitope spreading ( 2). Development of other classes of immunotherapies, such as cancer vaccines targeting neoantigens derived from genetic mutations, are making strides. For this purpose, it is important to efficiently induce tumor antigen-specific immunity. New treatment strategies are needed to increase the number of patients with long-term response. The combination with chemotherapy has also improved response rates and survival, however, an increase in synergistic long-term benefits compared with ICI alone was not shown ( 1) ( Figure 1 ). ICI can elicit long-term survival, called “tail-plateau”. Because of the limited response rate to ICI alone, combination therapies with other classes of drugs, including chemotherapy or molecular targeting agents, are currently being developed. Recent advances in immunotherapy, including the introduction of immune checkpoint inhibitors (ICI) and adoptive cell therapy, have changed the landscape of cancer care. Creative DC-targeted therapeutic strategies will be highlighted, including cancer vaccines and cell-based therapies. Finally, we discuss the impact of established therapies on DCs, such as immune checkpoint blockade. Immune checkpoint expression, small molecule mediators, metabolites, deprivation of pro-immunogenic and release of pro-tumorigenic cytokine secretion by tumors and tumor-attracted immuno-suppressive cells inhibit DC differentiation and function. We further focus on how cancer cells modulate DCs to escape from the host’s immune-surveillance. Here, we review the different subtypes and functions of DCs in the TME, including conventional DCs, plasmacytoid DC and the newly proposed subset, mregDC. Better understanding of DC impairment mechanisms in the TME will lead to more efficient DC-targeting immunotherapy. In this regard, the TME plays a major role in adversely affecting DC function. However, subsets of DCs also induce immune-tolerance, leading to tumor immune escape. They link innate to adaptive immunity by processing and presenting tumor antigens to T cells thereby initiating an anti-tumor response.
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