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

Abstract

Since the discovery of dendritic cells (DCs) by Ralph Steinmanand Zanvil Cohn 40years ago (1), the role of these cells as criticalregulators of immune tolerance versus activation has emerged asone of the most fundamental concepts in the field of immunol-ogy. Serving as a link between the innate and adaptive immunesystems, DCs exhibit sensitive immune surveillance capabilitiesthat enable their acquisition of antigens from a variety of sourcesin peripheral tissues, and they possess unique sensory propertiesand antigen processing machinery that enable their transforma-tion into potent antigen-presenting cells (APCs). Importantly, theoutcome (immune tolerance versus activation) of antigen pre-sentation to T cells by DC is dependent on the maturation andactivation state of the DC, and significant efforts over the last 20CyearshavethereforefocusedonunderstandingfactorsthatregulateDC maturation and activation. While their role in self-toleranceand the activation of T cell immunity to foreign pathogens haslong been appreciated, more recently DCs have also been shownto play important roles in the regulation of anti-tumor immuneresponses. Since this time, considerable efforts have been placedon understanding many facets of tumor-associated DC,including:the induction, regulation, and maintenance of anti-tumor immu-nity by DC; tumor-associated interference with these processes tosubvert anti-tumor immunity; and the application of this knowl-edgetodeveloptherapeuticstrategiesforimprovingDC-mediatedanti-tumor immune responses. In this collection of articles, wehighlight our current understanding of the role played by DCin anti-tumor immunity and focus attention on important ques-tions that remain to be answered in the field as we aim to improvethe immunogenicity of tumor-associated DC and the outcome ofDC-mediated anti-tumor immune responses in the future.We begin this research topic with an Opinion article by RolfZinkernagel (2) and a responding Commentary from Anne Hos-malin (3), who offer opposing views on cross-presentation oftumor antigen by DC that we believe will generate interestingand thoughtful discussion. These articles are followed by a con-tribution from Schiavoni et al. (4) reviewing the major subsets ofDC that have been implicated in cross-presentation and the roleof type I IFN in enhancing DC-mediated cross-priming of anti-tumor CD8C T cell responses. Research topic co-editor KristianHargadon then reviews the various levels at which tumor cells,tumor-derived factors, and tumor-associated cells in the milieuof the tumor microenvironment can interfere with DC function(5). Mechanistic insights into tumor-altered differentiation of DCprecursors, tumor-associated suppression of DC maturation andactivation, and tumor-induced development of regulatory DCwith immunosuppressive function are highlighted, as are recentimmunotherapeutic strategies that have been designed to pre-vent or overcome tumor-associated DC dysfunction and enhancethe quality of anti-tumor immune responses. Co-editor Timo-thy Bullock further examines the metabolic changes that occurin DC during their maturation and discusses how dysregulatedmetabolism, particularly at the level of glycolysis and fatty acidmetabolism,intumor-associatedDCmayalsoimpedematurationand contribute to the diminished immune stimulatory functionof these cells (6). The impact of tumors on DC maturation isalso explored by Dudek et al. (7), who describe the complex-ity of DC maturation status in the context of tumors, wherethe typical dichotomy of immature versus mature DC that reg-ulate immune tolerance versus activation against clearly “self” or“non-self” antigen is less obvious. The authors describe a contin-uum of DC maturation states reported in the context of tumorsthat include not only the classical immature, tolerogenic DCand mature, immunogenic DC but also semi-mature DC whichexpress low or even moderate levels of costimulatory moleculesbut which produce minimal stimulatory cytokines and there-fore potentiate either tolerogenic or pro-tumorigenic responses.Studies that have identified factors (cytokines/chemokines, celldeath modalities, and cancer cell-derived danger signals) regulat-ing tumor-associated DC function are highlighted, as is the abilityof anti-cancer therapeutic agents to influence and modulate thematuration states of DC.Additional discussion of this topic is pro-videdbyOttandBhardwaj(8),whospeculatehowtumorcelldeathresulting from MAPK pathway inhibition might enhance cross-presentation by DC in BRAF