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Simple Summary: Glioblastoma is known to be highly immunosuppressive in nature. Plasmacytoid dendritic cell infiltration is known to be associated with glioblastoma progression and promotes tumor immunosuppression. We provide important details to indicate that glioblastoma cell-secreted CCL21 plays a dual role both in recruiting plasmacytoid dendritic cells via binding to CCR7 and activating plasmacytoid dendritic cells through the CCR7/ACKR4—β-arrestin/CIITA pathway. Our result also provides a rationale to therapeutically target CCL21 as a potential novel treatment for glioblastoma. Dendritic cells (DCs) are professional antigen-presenting cells that are traditionally divided into two distinct subsets: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). pDCs are known for their ability to secrete large amounts of cytokine type I interferons (IFN- α). In our previous work, we have demonstrated that pDC infiltration promotes glioblastoma (GBM) tumor immunosuppression through decreased IFN-α secretion via TLR-9 signaling and increased suppressive function of regulatory T cells (Tregs) via increased IL-10 secretion, resulting in poor overall outcomes in mouse models of GBM. Further dissecting the overall mechanism of pDC-mediated GBM immunosuppression, in this study, we identified CCL21 as highly upregulated by multiple GBM cell lines, which recruit pDCs to tumor sites via CCL21-CCR7 signaling. Furthermore, pDCs are activated by CCL21 in the GBM microenvironment through intracellular signaling of β-arrestin and CIITA. Finally, we found that CCL21-treated pDCs directly suppress CD8+ T cell proliferation without affecting regulatory T cells (Tregs) differentiation, which is considered the canonical pathway of immunotolerant regulation. Taken together, our results show that pDCs play a multifaced role in GBM immunosuppression, and CCL21 could be a novel therapeutic target in GBM to overcome pDC-mediated immunosuppression. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastrointestinal (GI) tumors present a significant global health challenge, prompting the need for new therapeutic strategies. Plasmacytoid dendritic cells (pDCs) are crucial in tumor immunity, with both anti-tumor and pro-tumor effects. This review examines pDC roles in various GI tumors and their potential as therapeutic targets. In gastric cancer, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma, higher pDC infiltration correlates with worse outcomes, whereas in esophageal, pancreatic, and colorectal cancers, it improves outcomes. Overall, pDCs have a complex role in GI tumors, affecting both tumor immunity and progression. Further research is needed to refine their clinical use and explore combination therapies. Gastrointestinal (GI) tumors pose a significant global health burden, necessitating the exploration of novel therapeutic approaches. Plasmacytoid dendritic cells (pDCs) play a crucial role in tumor immunity, exhibiting both anti-tumor and pro-tumor effects. This review aims to summarize the role of pDCs in different types of GI tumors and assess their potential as therapeutic targets. In gastric cancer, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma, increased infiltration of pDCs was associated with a worse outcome, whereas in esophageal cancer, pancreatic cancer, and colorectal cancer, pDC infiltration improved the outcome. Initial animal studies of gastric cancer and hepatocellular carcinoma showed that pDCs could be a successful therapeutic target. In conclusion, pDCs play a multifaceted role in GI tumors, influencing both anti-tumor immunity and tumor progression. Further research is needed to optimize their clinical application and explore combinatorial approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: There are three main types of neoplastic plasmacytoid dendritic cell (pDC) proliferations: blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia with pDC differentiation (pDC-AML), and mature pDC proliferation (MPDCP). In this review, we focus on flow cytometry immunophenotyping analysis, discussing the immunophenotypes of each type of pDC proliferation, their differential diagnoses, and the challenges and pitfalls in evaluating these pDC proliferations. In this review, we aim to provide a summary of the diverse immunophenotypic presentations of distinct entities associated with plasmacytoid dendritic cell (pDC) proliferation. These entities include the following: (1) blastic plasmacytoid dendritic cell neoplasm (BPDCN); (2) mature pDC proliferation (MPDCP), most commonly seen in chronic myelomonocytic leukemia (CMML); and (3) myeloid neoplasms with pDC differentiation, in which pDCs show a spectrum of maturation from early immature pDCs to mature forms, most commonly seen in acute myeloid leukemia (pDC-AML). Our aim is to provide a flow cytometry diagnostic approach to these distinct and sometimes challenging entities and to clarify the immunophenotypic spectrum of neoplastic pDCs in different disease presentations. In this review, we also cover the strategies in the evaluation of residual disease, as well as the challenges and pitfalls we face in the setting of immune and targeted therapy. The differential diagnosis will also be discussed, as blasts in some AML cases can have a pDC-like immunophenotype, mimicking pDCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Plasmacytoid dendritic cells are the main type I interferon producing cells in humans and are able to modulate innate and adaptive immune responses. Tumor infiltration by plasmacytoid dendritic cells is already described and is associated with poor outcomes in cancers. In hematological diseases, Blastic Plasmacytoid Dendritic Cells Neoplasm (blastic counterpart) is well described, but little is known about tumor infiltration by mature plasmacytoid dendritic cells described in Myeloid Neoplasms (myeloid tumor cells and clonal pDC proliferation). This review provides a comprehensive overview of plasmacytoid dendritic cells in Myeloid Neoplasms. Plasmacytoid dendritic cells (pDC) are the main type I interferon producing cells in humans and are able to modulate innate and adaptive immune responses. Tumor infiltration by plasmacytoid dendritic cells is already well described and is associated with poor outcomes in cancers due to the tolerogenic activity of pDC. In hematological diseases, Blastic Plasmacytoid Dendritic Cells Neoplasm (BPDCN), aggressive leukemia derived from pDCs, is well described, but little is known about tumor infiltration by mature pDC described in Myeloid Neoplasms (MN). Recently, mature pDC proliferation (MPDCP) has been described as a differential diagnosis of BPDCN associated with acute myeloid leukemia (pDC-AML), myelodysplastic syndrome (pDC-MDS) and chronic myelomonocytic leukemia (pDC-CMML). Tumor cells are myeloid blasts and/or mature myeloid cells from related myeloid disorders and pDC derived from a clonal proliferation. The poor prognosis associated with MPDCP requires a better understanding of pDC biology, MN oncogenesis and immune response. This review provides a comprehensive overview about the biological aspects of pDCs, the description of pDC proliferation in MN, and an insight into putative therapies in pDC-AML regarding personalized medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute myeloid leukemia with plasmacytoid dendritic cell differentiation (pDC-AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are two leukemias characterized by neoplastic pDC proliferation. In this study, we aimed to explore the immunophenotypic and molecular profiles of pDC-AML and compare them with BPDCN. We found that pDCs in pDC-AML and BPDCN possessed different immunophenotype. The mutation profiles of these two were also different. These findings demonstrate that pDC-AML and BPDCN are two distinct entities and pDCs in these two entities derive from different subsets of pDC precursors. Acute myeloid leukemia (AML) with ≥2% plasmacytoid dendritic cells (pDC) has been recently described as AML with pDC differentiation (pDC-AML) characterized by pDC expansion with frequent RUNX1 mutations. In this study, we investigated a cohort of 53 pDC-AML cases representing about 3% of all AML cases. We characterized their immunophenotype and genetic profiles and compared these findings with blastic plasmacytoid dendritic cell neoplasm (BPDCN). pDC-differentiation/expansion was preferentially observed in AML with an immature myeloid or myelomonocytic immunophenotype, where myeloblasts were frequently positive for CD34 (98%), CD117 (94%), HLA-DR (100%) and TdT (79%), with increased CD123 (89%) expression. The median number of pDCs in pDC-AML was 6.6% (range, 2% to 26.3%) and their immunophenotype reminiscent of pDCs in early or intermediate stages of differentiation. The immunophenotype of pDCs in pDC-AML was different from BPDCN (n = 39), with major disparities in CD34 (96% vs. 0%), CD56 (8% vs. 97%) and TCL1 (12% vs. 98%) and significant differences in frequency of CD4, CD13, CD22, CD25, CD36, CD38, CD117 and CD303 expression. At the molecular level, the genetic landscapes of pDC-AML and BPDCN also differ, with RUNX1 mutations detected in 64% of pDC-AML versus 2% of BPDCN. Disparities in TET2 (21% vs. 56%), FLT3 (23% vs. 0%), DNMT3A (32% vs. 10%) and ZRSR2 (2% vs. 16%) (all p < 0.05) were also detected. The distinct immunophenotypic and mutation profiles of pDC-AML and BPDCN indicate that the neoplastic pDCs in pDC-AML and BPDCN derived from different subsets of pDC precursors. [ABSTRACT FROM AUTHOR]

The introduction of targeted therapies and immunotherapies has significantly improved the outcome of metastatic melanoma (MM) patients. These approaches rely on immune functions for their anti-melanoma response. Plasmacytoid dendritic cells (pDCs) exhibit anti-tumor function by production of effector molecules, type I interferons (I-IFNs), and cytokines. Tissue and blood pDCs result compromised in MM, although these findings are still partially conflicting. This study reports that blood pDCs were dramatically depleted in MM, particularly in patients with high lactate dehydrogenase (LDH) and high tumor burden; the reduced pDC frequency was associated with poor overall survival. Circulating pDCs resulted also in significant impairment in interferon alpha (IFN-α) and C-X-C motif chemokine 10 (CXCL10) production in response to toll-like receptor (TLR)-7/8 agonists; on the contrary, the response to TLR-9 agonist remained intact. In the BRAFV600+ subgroup, no recovery of pDC frequency could be obtained by BRAF and MEK inhibitors (BRAFi; MEKi), whereas their function was partially rescued. Mechanistically, in vitro exposure to lactic acidosis impaired both pDC viability and function. In conclusion, pDCs from MM patients were found to be severely impaired, with a potential role for lactic acidosis. Short-term responses to treatments were not associated with pDC recovery, suggesting long-lasting effects on their compartment. [ABSTRACT FROM AUTHOR]

The immune response, both innate and adaptive, is a key player in cancer development and progression. Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells that play one of the central roles in the immune system. They are known mostly as the major IFN type I-producing cells upon stimulation of Toll-like receptors 7 and 9. However, based on current knowledge, the functionality of pDCs is very complex, as they have the ability to affect many other cell types. In the context of the tumor tissue, pDCs were mostly described to show substantial functional defects and therefore contribute to the establishement of immunosuppressive tumor microenvironment. Immunotherapeutic approaches have proven to be one of the most promising treatment strategies in the last decade. In view of this fact, it is crucial to map the complexity of the tumor microenvironment in detail, including less numerous cell types. This review focuses on pDCs in relation to solid tumors. We provide a summary of current data on the role of pDCs in different tumor types and suggest their possible clinical applications. [ABSTRACT FROM AUTHOR]