The Role of Tumor/Dendritic Cell Interactions in the Regulation of Anti-Tumor Immunity: The Good, the Bad, and the Ugly

Since the discovery of dendritic cells (DCs) by Ralph Steinman and Zanvil Cohn 40 years ago (1), the role of these cells as critical regulators of immune tolerance versus activation has emerged as one of the most fundamental concepts in the field of immunology. Serving as a link between the innate and adaptive immune systems, DCs exhibit sensitive immune surveillance capabilities that enable their acquisition of antigens from a variety of sources in peripheral tissues, and they possess unique sensory properties and antigen processing machinery that enable their transformation into potent antigen-presenting cells (APCs). Importantly, the outcome (immune tolerance versus activation) of antigen presentation to T cells by DC is dependent on the maturation and activation state of the DC, and significant efforts over the last 20+ years have therefore focused on understanding factors that regulate DC maturation and activation. While their role in self-tolerance and the activation of T cell immunity to foreign pathogens has long been appreciated, more recently DCs have also been shown to play important roles in the regulation of anti-tumor immune responses. Since this time, considerable efforts have been placed on understanding many facets of tumor-associated DC, including: the induction, regulation, and maintenance of anti-tumor immunity by DC; tumor-associated interference with these processes to subvert anti-tumor immunity; and the application of this knowledge to develop therapeutic strategies for improving DC-mediated anti-tumor immune responses. In this collection of articles, we highlight our current understanding of the role played by DC in anti-tumor immunity and focus attention on important questions that remain to be answered in the field as we aim to improve the immunogenicity of tumor-associated DC and the outcome of DC-mediated anti-tumor immune responses in the future. We begin this research topic with an Opinion article by Rolf Zinkernagel (2) and a responding Commentary from Anne Hosmalin (3), who offer opposing views on cross-presentation of tumor antigen by DC that we believe will generate interesting and thoughtful discussion. These articles are followed by a contribution from Schiavoni et al. (4) reviewing the major subsets of DC that have been implicated in cross-presentation and the role of type I IFN in enhancing DC-mediated cross-priming of antitumor CD8+ T cell responses. Research topic co-editor Kristian Hargadon then reviews the various levels at which tumor cells, tumor-derived factors, and tumor-associated cells in the milieu of the tumor microenvironment can interfere with DC function (5). Mechanistic insights into tumor-altered differentiation of DC precursors, tumor-associated suppression of DC maturation and activation, and tumor-induced development of regulatory DC with immunosuppressive function are highlighted, as are recent immunotherapeutic strategies that have been designed to prevent or overcome tumor-associated DC dysfunction and enhance the quality of anti-tumor immune responses. Co-editor Timothy Bullock further examines the metabolic changes that occur in DC during their maturation and discusses how dysregulated metabolism, particularly at the level of glycolysis and fatty acid metabolism, in tumor-associated DC may also impede maturation and contribute to the diminished immune stimulatory function of these cells (6). The impact of tumors on DC maturation is also explored by Dudek et al. (7), who describe the complexity of DC maturation status in the context of tumors, where the typical dichotomy of immature versus mature DC that regulate immune tolerance versus activation against clearly “self” or “non-self” antigen is less obvious. The authors describe a continuum of DC maturation states reported in the context of tumors that include not only the classical immature, tolerogenic DC and mature, immunogenic DC but also semi-mature DC which express low or even moderate levels of costimulatory molecules but which produce minimal stimulatory cytokines and therefore potentiate either tolerogenic or pro-tumorigenic responses. Studies that have identified factors (cytokines/chemokines, cell death modalities, and cancer cell-derived danger signals) regulating tumor-associated DC function are highlighted, as is the ability of anti-cancer therapeutic agents to influence and modulate the maturation states of DC. Additional discussion of this topic is provided by Ott and Bhardwaj (8),who speculate how tumor cell death resulting from MAPK pathway inhibition might enhance crosspresentation by DC in BRAFV600 mutant melanoma patients, and by Palombo et al. (9), who describe various danger-associated molecular patterns (DAMPs) released during immunogenic cancer cell death that stimulate inflammatory DC to activate tumorspecific CD8+ T cell responses. This latter Perspective article