Plasmacytoid dendritic cells (pDC) are innate bone marrow derived immune cells found in the peripheral blood and lymphoid organs. They home to inflamed peripheral tissues in different disease states including cancer by chemotactic stimuli. PDCs are multifaceted immune cells executing various innate ...
Plasmacytoid dendritic cells (pDC) are innate bone marrow derived immune cells found in the peripheral blood and lymphoid organs. They home to inflamed peripheral tissues in different disease states including cancer by chemotactic stimuli. PDCs are multifaceted immune cells executing various innate immunological functions. Their first line of defence consists in type I interferons (I-IFN) production upon nucleic acids sensing through endosomal Toll-like receptor (TLR) 7- and 9-dependent signalling pathways. Besides TLRs, human pDCs express different nucleic acid sensors, such as C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), and cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS). In the last few years, different studies have reported that pDCs are also able to sense cytosolic DNA through cGAS–STING pathway eliciting a potent I-IFN production independently of TLR7/9. pDCs are also endowed with direct effector functions. Type I IFNs are a class of proinflammatory cytokines that have context-dependent functions on cancer immunosurveillance and immunoediting. Specifically, robust, acute, and ultimately resolving I-IFN responses have been shown to participate in cancer immunosurveillance, whereas weak, sub-optimal, and chronic I-IFN signaling support tumor progression and resistance to therapy by cancer cell-intrinsic effects. pDCs have been detected in a wide variety of human neoplasms, including carcinomas, cutaneous melanoma and lymphoma. Tumor associated pDCs (TA-pDCs) are recruited at the tumor site by chemokines released by cancer cells or by the tumor microenvironment (TME). Although the role of pDCs in cancer immunoediting/immune surveillance is still poorly understood, their spontaneous activation has been rarely documented. Accordingly, their presence of pDCs in the TME has been associated to a tolerogenic phenotype leading to low I-IFN production and generation of regulatory T cells (Treg) and increased expression of immunomodulatory molecules (e.g. IDO). This functional state could be induced by immunosuppressive cytokines or oncometabolites, as recently reported. Novel treatment options leading to pDCs activation and disrupting the immunosuppressive TME, might be able to reprogramme TA-pDCs with a relevant clinical benefit. In addition to I-IFN production, pDCs could exert direct effector functions. By TLR-7/9 engagement, activated pDCs could exert killing capacities via the upregulation of TRAIL. Moreover, GrB is constitutively expressed in human pDCs, but its production and release is further induced by cytokines abundant in cancer tissues. However, the role of this pDC ability in cancer immunosurveillance is still largely unexplored.
The scope of this collection is to accommodate studies exploring the role of human pDC in cancer immunity and mainly challenging some remaining important issues related to:
1) a more comprehensive definition of TA-PDC;
2) the level and heterogeneity of endogenous PDC activation in blood and tissue of cancer patients;
3) identification of relevant immune escape mechanisms induced by TME in human cancer and
4) efficacy and mechanisms of novel treatment option modulating pDC functions.
Along these lines manuscripts investigating the clinical relevance of circulating and tissue pDC enumeration, cell interactions and resulting functions during neoadjuvant immunotherapy treatment are welcome. Data integration showing single cell approaches and spatial resolution of cancer tissues are highly recommended.
Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this topic.
Keywords:
plasmacytoid dendritic cells, cancer, type I interferon, TLR7, TLR9, cGAS–STING, spatial transcriptomics, multiplex immunostaining, TLR-agonist, STING-agonist
Important Note:
All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.