The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models (original) (raw)
Related papers
Plasmacytoid dendritic cells and cancer
2011
Cancer develops in a complex microenvironment comprising cancer cells, stromal cells, and host immune cells with their soluble products. The counteracting host-protective and tumor-promoting roles of different immune cell populations have been elegantly clarified in the last decade by pertinent genetically modified mouse models. Among cells with a potential role in cancer immunity, PDCs might represent important players as a result of their capacity to bring together innate and adaptive immunity. This review summarizes current knowledge about the role of PDCs in cancer immunity. PDCs have been documented in primary and metastatic human neoplasms; however, the clinical significance of this finding is still unknown. Once into the tumor bed, PDCs can be hijacked by the tumor microenvironment and lose their propensity to produce the required amount of endogenous I-IFN. However, when properly reprogrammed (i.e., by TLR agonists), PDCs might mediate tumor rejection in a clinical setting. Tumor rejection, at least partially, is driven by I-IFN and seems to require a cross-talk with other innate immune cells, including IFN DCs. The latter evidence, although still limited to skin cancers, can provide a leading model for developing adjuvant immune therapy for other neoplasms. To this end, the generation of appropriate mouse models to modulate the frequency and activation state of murine PDCs will also be of remarkable importance.
A novel dendritic cell subset involved in tumor immunosurveillance
Nature Medicine, 2006
The interferon (IFN)-c-induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice 1,2 . Here we show that the main source of IFN-c is not the conventional NK cell but a subset of B220 + Ly6Cdendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220 + NK1.1 + dendritic cells secrete high levels of IFN-c and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumorbearing Rag2 -/-Il2rg -/mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.
The Role of Plasmacytoid Dendritic Cells in Cancers
Frontiers in Immunology, 2021
Plasmacytoid dendritic cells (pDCs) are a special subtype of dendritic cells with the morphology of plasma cells. pDCs produce massive amounts of type I interferon (IFN-I), which was originally found to play an extremely pivotal role in antiviral immunity. Interestingly, accumulated evidence indicates that pDCs can also play an important role in tumorigenesis. In the human body, most of the IFN-α is secreted by activated pDCs mediated by toll-like receptor (TLR) stimulation. In many types of cancer, tumors are infiltrated by a large number of pDCs, however, these pDCs exhibit no response to TLR stimulation, and reduced or absent IFN-α production. In addition, tumor-infiltrating pDCs promote recruitment of regulatory T cells (Tregs) into the tumor microenvironment, leading to immunosuppression and promoting tumor growth. In this review, we discuss recent insights into the development of pDCs and their roles in a variety of malignancies, with special emphasis on the basic mechanisms.
Journal of Clinical Investigation, 2008
A prerequisite for strong adaptive antiviral immunity is the robust initial activation of the innate immune system, which is frequently mediated by TLR-activated plasmacytoid DCs (pDCs). Natural antitumor immunity is often comparatively weak, potentially due to the lack of TLR-mediated activation signals within the tumor microenvironment. To assess whether pDCs are capable of directly facilitating effective antitumor immune responses, mice bearing established subcutaneous B16 melanoma tumors were administered TLR9-activated pDCs directly into the tumor. We found that TLR9-activated pDCs induced robust, spontaneous CTL crosspriming against multiple B16 tumor antigens,
Tumor Promotion by Intratumoral Plasmacytoid Dendritic Cells Is Reversed by TLR7 Ligand Treatment
Cancer Research, 2013
Plasmacytoid dendritic cells (pDC) are key regulators of antiviral immunity. In previous studies, we reported that pDC-infiltrating human primary breast tumors represent an independent prognostic factor associated with poor outcome. To understand this negative impact of tumor-associated pDC (TApDC), we developed an orthotopic murine mammary tumor model that closely mimics the human pathology, including pDC and regulatory T cell (Treg) infiltration. We showed that TApDC are mostly immature and maintain their ability to internalize antigens in vivo and to activate CD4 þ T cells. Most importantly, TApDC were specifically altered for cytokine production in response to Toll-like receptor (TLR)-9 ligands in vitro while preserving unaltered response to TLR7 ligands (TLR7L). In vivo pDC depletion delayed tumor growth, showing that TApDC provide an immunesubversive environment, most likely through Treg activation, thus favoring tumor progression. However, in vivo intratumoral administration of TLR7L led to TApDC activation and displayed a potent curative effect. Depletion of pDC and type I IFN neutralization prevented TLR7L antitumoral effect. Our results establish a direct contribution of TApDC to primary breast tumor progression and rationalize the application of TLR7 ligands to restore TApDC activation in breast cancer. Cancer Res; 73(15); 4629-40. Ó2013 AACR.
Plasmacytoid dendritic cells and their therapeutic activity in cancer
OncoImmunology, 2012
In the last decade several studies provided evidence that plasmacytoid dendritic cells (pDCs) infiltrate human neoplasms with poor prognosis. However, the role of tumor-associated pDCs remains controversial. Various studies indicate that pDCs play an immuno-suppressive role and facilitate tumor progression in both animal models and humans. In contrast, others found that the presence of activated tumor-associated pDCs results in tumor regression in mice. Given these findings, understanding pDC function in tumor biology is an important necessity and may pave the way for novel therapeutic strategies to fight malignancies.
A lymph node-to-tumour PDL1+macrophage circuit antagonizes dendritic cell immunotherapy
ABSTRACTImmune-checkpoint blockers (ICB) provide limited benefit against T cell-depleted tumours, calling for therapeutic innovation. Here, we aimed at designing a new type of dendritic cell (DC) vaccine by unbiased computational integration of multi-omics data from cancer patients. In a first attempt, a DC vaccine designed to present tumor antigens from cancer cells succumbing to immunogenic cancer cell death (ICD) and to elicit high type I interferon (IFN) responses failed to induce the regression of mouse tumors lacking T cell infiltrates. In lymph nodes (LNs), instead of activating CD4+and CD8+T cells, DCs stimulated immunosuppressive PD-L1+LN-associated macrophages (LAMs) via a type I IFN response. Moreover, DC vaccines of this type stimulated pre-existing, T cell-suppressive, PD-L1+tumour-associated macrophages (TAMs). This created a T cell-suppressive circuit of PD-L1+macrophages, spanning across LNs and tumours. Accordingly, DC vaccines synergised with PD-L1 blockade to depl...
Journal of Leukocyte Biology, 2005
Plasmacytoid dendritic cells (PDC) constitute a distinct subset of DC found in human peripheral lymph nodes (LN), but little is known about their function. Cell suspensions were prepared from tumor draining LN (n)02؍ and control LN (n)11؍ of women undergoing surgical resection for primary breast cancer and elective surgery for benign conditions, respectively. Using fourcolor flow cytometry, human leukocyte antigen-DR ؉ DC subsets were identified phenotypically. The proportions and numbers of cells innately producing interleukin (IL)-4, IL-10, IL-12, and interferon-␥ (IFN-␥) were also measured from intracellular accumulation of cytokine after blocking with monensin. All flow cytometry data were collected without compensation and were compensated offline using the Winlist algorithm (Verity software). This package also provided the subtraction program to calculate percentage positive cells and intensity of staining. PDC (CD11c-, CD123 ؉) expressed more cytokines than did myeloid DC (CD11c ؉) or CD1a ؉ putative "migratory" DC (P<0.001). LN PDC from patients with a good prognosis (px; n)11؍ demonstrated a relative increase in IL-12 and IFN-␥ expression (median IL-10:IL-12 ratio87.0؍ and median IL-4:IFN-␥ ra-tio,)7.0؍ and PDC from LN draining poor px cancer (n)9؍ showed a relative increase in IL-10 and IL-4 expression (median IL-10:IL-12 ratio13.1؍ and median IL-4:IFN-␥ ratio.)6.2؍ The difference in IL-4:IFN-␥ expression between good and poor px cancer groups was significant (P<0.05). Thus, PDC innately producing cytokines were identified in cell suspensions from human LN, and the character of PDC cytokine secretion may differ between two breast cancer prognostic groups. We speculate that a shift towards PDC IL-10 and IL-4 expression could promote tumor tolerance in LN draining poor px breast cancer.
Physiological Role of Plasmacytoid Dendritic Cells and Their Potential Use in Cancer Immunity
Clinical and Developmental Immunology, 2008
Dendritic cells (DCs) play a pivotal role in the control of innate and adaptive immune responses. They are a heterogeneous cell population, where plasmacytoid dendritic cells (pDCs) are a unique subset capable of secreting high levels of type I IFNs. It has been demonstrated that pDCs can coordinate events during the course of viral infection, atopy, autoimmune diseases, and cancer. Therefore, pDC, as a main source of type I IFN, is an attractive target for therapeutic manipulations of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies. The therapeutic vaccination with antigen-pulsed DCs has shown a limited efficacy to generate an effective long-lasting immune response against tumor cells. A rational manipulation and design of vaccines which could include DC subsets outside "Langerhans cell paradigm" might allow us to improve the therapeutic approaches for cancer patients.
A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments
Nature medicine, 2018
Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased o...