Dendritic cells (DCs) exhibit a specialized antigen-presenting function and play crucial roles in both innate and adaptive immune responses. Due to their ability to cross-present tumor cell-associated antigens to naïve T cells, DCs are instrumental in the generation of specific T-cell-mediated antitumor effector responses in the control of tumor growth and tumor cell dissemination. Within an immunosuppressive tumor microenvironment, DC antitumor functions can, however, be severely impaired. In this review, we focus on the mechanisms of DC capture and activation by tumor cell antigens and the role of the tumor microenvironment in shaping DC functions, taking advantage of recent studies showing the phenotype acquisition, transcriptional state and functional programs revealed by scRNA-seq analysis. The therapeutic potential of DC-mediated tumor antigen sensing in priming antitumor immunity is also discussed.

Immature monocyte-derived dendritic cells (DC) strongly express the endocytic mannose receptor (MR). Addition of a specific anti-MR mAb (clone PAM-1) for 24 h to cultures of immature DC induced phenotypical and functional maturation of the cells, assessed as up-regulation of costimulatory molecules and CD83, and chemotactic response to CCL19. A different isotype-matched anti-MR mAb (clone 19.2) had no significant effect. Engagement of MR with mAb PAM-1 induced the production of the anti-inflammatory cytokines IL-10, IL-1R antagonist, and of the nonsignaling IL-1R type II. In contrast IL-1β, TNF, and IL-12 were not produced. PAM-1-treated DC were unable to polarize Th1 effector cells and did not secrete the chemokines CXCL10 and CCL19; in turn, they produced large amounts of CCL22 and CCL17, thus favoring the amplification of Th2 circuits. T cells cocultured with PAM-1-matured DC initially proliferated but later became anergic and behaved as suppressor/regulatory cells. Natural ligands binding to MR had differential effects. MUC III (a partially purified mucin), biglycan (a purified complex proteoglycan), and mannosylated lipoarabinomannan from Mycobacterium tuberculosis affected cytokine production with high IL-10, IL-1R antagonist, IL-1R type II, and inhibition of IL-12. In contrast, mannan, dextran, and thyroglobulin had no significant effect. In conclusion, the appropriate engagement of the MR by mAb PAM-1 and selected natural ligands elicit a secretory program in mono-derived DC characterized by a distinct profile of cytokines/chemokines with the ability to dampen inflammation and to inhibit the generation of Th1-polarized immune responses.

Accumulating evidence shows that chronic inflammation is associated to increased risk of cancer. An inflammatory component is present also in the microenvironment of tumours epidemiologically unrelated to inflammation. Extensive investigations over the past decade have uncovered many of the important mechanistic pathways underlying cancer-related inflammation. Pathways linking inflammation and cancer have been identified: an intrinsic one (driven by genetic events that cause neoplasia) and an extrinsic one (driven by inflammatory conditions which predispose to cancer). Smouldering inflammation is a component of the tumour microenvironment and is a recognized hallmark of cancer. Key orchestrators at the intersection of the intrinsic and extrinsic pathways include transcription factors (e.g. Nuclear Factor kappa-B, NFKB) that modulate the inflammatory response through soluble mediators (cytokines, chemokines) and cellular components (e.g. tumor-associated macrophages), promoting tumorigenesis. NFKB aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immunity, and alters responses to hormones and chemotherapeutic agents. Emerging evidence also suggests that persistent inflammation promotes genetic instability. Thus, cancer-related inflammation represents a target for innovative diagnostic and therapeutic strategies.

Gene‐targeted mice were used to evaluate the role of the gamma isoform of phosphoinositide 3‐kinase (PI3Kγ) in dendritic cell (DC) migration and induction of specific T‐cell‐mediated immune responses. DC obtained from PI3Kγ−/− mice showed a reduced ability to respond to chemokines in vitro and ex vivo and to travel to draining lymph nodes under inflammatory conditions. PI3Kγ−/− mice had a selective defect in the number of skin Langerhans cells and in lymph node CD8α− DC. Furthermore, PI3Kγ−/− mice showed a defective capacity to mount contact hypersensitivity and delayed‐type hypersensitivity reactions. This defect was directly related to the reduced ability of antigen‐loaded DC to migrate from the periphery to draining lymph nodes. Thus, PI3Kγ plays a nonredundant role in DC trafficking and in the activation of specific immunity. Therefore, PI3Kγ may be considered a new target to control exaggerated immune reactions.

The inflammatory and IFN pathways of innate immunity play a key role in the resistance and pathogenesis of coronavirus disease 2019 (COVID-19). Innate sensors and SARS-CoV-2–associated molecular patterns (SAMPs) remain to be completely defined. Here, we identified single-stranded RNA (ssRNA) fragments from the SARS-CoV-2 genome as direct activators of endosomal TLR7/8 and MyD88 pathway. The same sequences induced human DC activation in terms of phenotype and function, such as IFN and cytokine production and Th1 polarization. A bioinformatic scan of the viral genome identified several hundreds of fragments potentially activating TLR7/8, suggesting that products of virus endosomal processing potently activate the IFN and inflammatory responses downstream of these receptors. In vivo, SAMPs induced MyD88-dependent lung inflammation characterized by accumulation of proinflammatory and cytotoxic mediators and immune cell infiltration, as well as splenic DC phenotypical maturation. These results identified TLR7/8 as a crucial cellular sensor of ssRNAs encoded by SARS-CoV-2 involved in host resistance and the disease pathogenesis of COVID-19.