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Advanced Science (Weinheim,... Nov 2023The efficient activation of professional antigen-presenting cells-such as dendritic cells (DC)-in tumors and lymph nodes is critical for the design of next-generation...
The efficient activation of professional antigen-presenting cells-such as dendritic cells (DC)-in tumors and lymph nodes is critical for the design of next-generation cancer vaccines and may be able to provide anti-tumor effects by itself through immune stimulation. The challenge is to stimulate these cells without causing excessive toxicity. It is hypothesized that a multi-pronged combinatorial approach to DC stimulation would allow dose reductions of innate immune receptor-stimulating TLR3 agonists while enhancing drug efficacy. Here, a hybrid lipid nanoparticle (LNP) platform is developed and tested for double-stranded RNA (polyinosinic:polycytidylic acid for TLR3 agonism) and immune modulator (L-CANDI) delivery. This study shows that the ≈120 nm hybrid nanoparticles-in-nanoparticles effectively eradicate tumors by themselves and generate long-lasting, durable anti-tumor immunity in mouse models.
Topics: Animals; Mice; Toll-Like Receptor 3; Poly I-C; Cancer Vaccines; Neoplasms; Dendritic Cells
PubMed: 37814359
DOI: 10.1002/advs.202303576 -
Cell Reports. Medicine Jan 2024Current immunotherapies provide limited benefits against T cell-depleted tumors, calling for therapeutic innovation. Using multi-omics integration of cancer patient...
Current immunotherapies provide limited benefits against T cell-depleted tumors, calling for therapeutic innovation. Using multi-omics integration of cancer patient data, we predict a type I interferon (IFN) response state of dendritic cell (DC) vaccines, with efficacious clinical impact. However, preclinical DC vaccines recapitulating this state by combining immunogenic cancer cell death with induction of type I IFN responses fail to regress mouse tumors lacking T cell infiltrates. Here, in lymph nodes (LNs), instead of activating CD4/CD8 T cells, DCs stimulate immunosuppressive programmed death-ligand 1-positive (PD-L1) LN-associated macrophages (LAMs). Moreover, DC vaccines also stimulate PD-L1 tumor-associated macrophages (TAMs). This creates two anatomically distinct niches of PD-L1 macrophages that suppress CD8 T cells. Accordingly, a combination of PD-L1 blockade with DC vaccines achieves significant tumor regression by depleting PD-L1 macrophages, suppressing myeloid inflammation, and de-inhibiting effector/stem-like memory T cells. Importantly, clinical DC vaccines also potentiate T cell-suppressive PD-L1 TAMs in glioblastoma patients. We propose that a multimodal immunotherapy and vaccination regimen is mandatory to overcome T cell-depleted tumors.
Topics: Humans; Animals; Mice; CD8-Positive T-Lymphocytes; B7-H1 Antigen; Macrophages; Glioblastoma; Dendritic Cells; Lymph Nodes; Vaccines
PubMed: 38232703
DOI: 10.1016/j.xcrm.2023.101377 -
Cancer Biology & Medicine Oct 2023Plasmacytoid dendritic cells (pDCs) are a pioneer cell type that produces type I interferon (IFN-I) and promotes antiviral immune responses. However, they are... (Review)
Review
Plasmacytoid dendritic cells (pDCs) are a pioneer cell type that produces type I interferon (IFN-I) and promotes antiviral immune responses. However, they are tolerogenic and, when recruited to the tumor microenvironment (TME), play complex roles that have long been a research focus. The interactions between pDCs and other components of the TME, whether direct or indirect, can either promote or hinder tumor development; consequently, pDCs are an intriguing target for therapeutic intervention. This review provides a comprehensive overview of pDC crosstalk in the TME, including crosstalk with various cell types, biochemical factors, and microorganisms. An in-depth understanding of pDC crosstalk in TME should facilitate the development of novel pDC-based therapeutic methods.
Topics: Humans; Neoplasms; Dendritic Cells; Tumor Microenvironment
PubMed: 37817484
DOI: 10.20892/j.issn.2095-3941.2023.0241 -
Genes Nov 2023The dendritic cell (DC) vaccine anti-cancer strategy involves tumour-associated antigen loading and maturation of autologous ex vivo cultured DCs, followed by infusion... (Review)
Review
The dendritic cell (DC) vaccine anti-cancer strategy involves tumour-associated antigen loading and maturation of autologous ex vivo cultured DCs, followed by infusion into the cancer patient. This strategy stemmed from the idea that to induce a robust anti-tumour immune response, it was necessary to bypass the fundamental immunosuppressive mechanisms of the tumour microenvironment that dampen down endogenous innate immune cell activation and enable tumours to evade immune attack. Even though the feasibility and safety of DC vaccines have long been confirmed, clinical response rates remain disappointing. Hence, the full potential of DC vaccines has yet to be reached. Whether this cellular-based vaccination approach will fully realise its position in the immunotherapy arsenal is yet to be determined. Attempts to increase DC vaccine immunogenicity will depend on increasing our understanding of DC biology and the signalling pathways involved in antigen uptake, maturation, migration, and T lymphocyte priming to identify amenable molecular targets to improve DC vaccine performance. This review evaluates various genetic engineering strategies that have been employed to optimise and boost the efficacy of DC vaccines.
Topics: Humans; Vaccine Efficacy; T-Lymphocytes; Neoplasms; Dendritic Cells; Vaccines; Tumor Microenvironment
PubMed: 38136940
DOI: 10.3390/genes14122118 -
Proceedings of the National Academy of... Aug 2023Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2....
Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2. Murine and human cDC1 share the mRNA expression of XCR1. Murine studies indicated a specific role of the XCR1-XCL1 axis in the induction of immune responses. Here, we describe that human cDC1 can be distinguished into XCR1 and XCR1 cDC1 in lymphoid as well as nonlymphoid tissues. Steady-state XCR1 cDC1 display a preactivated phenotype compared to XCR1 cDC1. Upon stimulation, XCR1 cDC1, but not XCR1 cDC1, secreted high levels of inflammatory cytokines as well as chemokines. This was associated with enhanced activation of NK cells mediated by XCR1 cDC1. Moreover, XCR1 cDC1 excelled in inhibiting replication of Influenza A virus. Further, under DC differentiation conditions, XCR1 cDC1 developed into XCR1 cDC1. After acquisition of XCR1 expression, XCR1 cDC1 secreted comparable level of inflammatory cytokines. Thus, XCR1 is a marker of terminally differentiated cDC1 that licenses the antiviral effector functions of human cDC1, while XCR1 cDC1 seem to represent a late immediate precursor of cDC1.
Topics: Humans; Cell Differentiation; Cytokines; Dendritic Cells; Killer Cells, Natural
PubMed: 37566635
DOI: 10.1073/pnas.2300343120 -
ELife Aug 2023Cancer immunotherapies, in particular checkpoint blockade immunotherapy (CBT), can induce control of cancer growth, with a fraction of patients experiencing durable...
Cancer immunotherapies, in particular checkpoint blockade immunotherapy (CBT), can induce control of cancer growth, with a fraction of patients experiencing durable responses. However, the majority of patients currently do not respond to CBT and the molecular determinants of resistance have not been fully elucidated. Mounting clinical evidence suggests that the clonal status of neoantigens (NeoAg) impacts the anti-tumor T cell response. High intratumor heterogeneity (ITH), where the majority of NeoAgs are expressed subclonally, is correlated with poor clinical response to CBT and poor infiltration with tumor-reactive T cells. However, the mechanism by which ITH blunts tumor-reactive T cells is unclear. We developed a transplantable murine lung cancer model to characterize the immune response against a defined set of NeoAgs expressed either clonally or subclonally to model low or high ITH, respectively. Here we show that clonal expression of a weakly immunogenic NeoAg with a relatively strong NeoAg increased the immunogenicity of tumors with low but not high ITH. Mechanistically we determined that clonal NeoAg expression allowed cross-presenting dendritic cells to acquire and present both NeoAgs. Dual NeoAg presentation by dendritic cells was associated with a more mature DC phenotype and a higher stimulatory capacity. These data suggest that clonal NeoAg expression can induce more potent anti-tumor responses due to more stimulatory dendritic cell:T cell interactions. Therapeutic vaccination targeting subclonally expressed NeoAgs could be used to boost anti-tumor T cell responses.
Topics: Animals; Mice; Cross-Priming; Antigens, Neoplasm; Lung Neoplasms; T-Lymphocytes; Dendritic Cells
PubMed: 37548358
DOI: 10.7554/eLife.85263 -
Nature Communications Oct 2023Type 1 conventional dendritic cells (cDC1) are the most efficient cross-presenting cells that induce protective cytotoxic T cell response. However, the regulation of...
Type 1 conventional dendritic cells (cDC1) are the most efficient cross-presenting cells that induce protective cytotoxic T cell response. However, the regulation of their homeostasis and function is incompletely understood. Here we observe a selective reduction of splenic cDC1 accompanied by excessive cell death in mice with Zeb1 deficiency in dendritic cells, rendering the mice more resistant to Listeria infection. Additionally, cDC1 from other sources of Zeb1-deficient mice display impaired cross-presentation of exogenous antigens, compromising antitumor CD8 T cell responses. Mechanistically, Zeb1 represses the expression of microRNA-96/182 that target Cybb mRNA of NADPH oxidase Nox2, and consequently facilitates reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytosol. Cybb re-expression in Zeb1-deficient cDC1 fully restores the defective cross-presentation while microRNA-96/182 overexpression in Zeb1-sufficient cDC1 inhibits cross-presentation. Therefore, our results identify a Zeb1-microRNA-96/182-Cybb pathway that controls cross-presentation in cDC1 and uncover an essential role of Zeb1 in cDC1 homeostasis.
Topics: Animals; Mice; Antigens; CD8-Positive T-Lymphocytes; Dendritic Cells; Homeostasis; MicroRNAs; Transcription Factors
PubMed: 37863917
DOI: 10.1038/s41467-023-42428-7 -
Frontiers in Immunology 2023Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and treatment resistant cancers. Due to its desmoplastic and hypoxic nature along with an abundance of...
INTRODUCTION
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and treatment resistant cancers. Due to its desmoplastic and hypoxic nature along with an abundance of myeloid cell infiltration and scarce T cell infiltration, PDAC is considered a cold tumor.
METHODS
Here we sought to investigate myeloid cell infiltration and composition in PDAC spheroids by targeting the hypoxia-associated pathways endoplasmic reticulum oxidoreductase 1 alpha (ERO1a) and indoleamine 2,3-dioxygenase 1 (IDO1). Using MiaPaCa2 spheroids with hypoxic core, we assessed the roles of ERO1a and IDO1 inhibition in modulating monocyte infiltration and differentiation, followed by characterizing immunomodulatory factors secreted using LC-MS/MS.
RESULTS
Inhibition of ERO1a and IDO1 significantly improved monocyte infiltration and differentiation into dendritic cells. LC-MS/MS analysis of the PDAC spheroid secretome identified downregulation of hypoxia and PDAC pathways, and upregulation of antigen presentation pathways upon inhibition of ERO1a and IDO1. Furthermore, immunomodulatory factors involved in immune infiltration and migration including interleukin-8, lymphocyte cytosolic protein 1, and transgelin-2, were upregulated upon inhibition of ERO1a and IDO1.
DISCUSSION
Collectively, our results show that inhibition of ERO1a and IDO1 modulates the tumor microenvironment associated with improved monocyte infiltration and differentiation into dendritic cells to potentially influence therapeutic responses in patients with PDAC.
Topics: Humans; Chromatography, Liquid; Tandem Mass Spectrometry; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Hypoxia; Dendritic Cells; Tumor Microenvironment
PubMed: 38187398
DOI: 10.3389/fimmu.2023.1264012 -
Frontiers in Immunology 2023
Topics: Humans; Immunologic Factors; Adjuvants, Immunologic; Phenotype; Dendritic Cells
PubMed: 38193089
DOI: 10.3389/fimmu.2023.1353765 -
Biology Direct Nov 2023Cancer immunotherapy, alone or in combination with conventional therapies, has revolutionized the landscape of antineoplastic treatments, with dendritic cells (DC)... (Review)
Review
Cancer immunotherapy, alone or in combination with conventional therapies, has revolutionized the landscape of antineoplastic treatments, with dendritic cells (DC) emerging as key orchestrators of anti-tumor immune responses. Among the distinct DC subsets, conventional type 1 dendritic cells (cDC1) have gained prominence due to their unique ability to cross-present antigens and activate cytotoxic T lymphocytes. This review summarizes the distinctive characteristics of cDC1, their pivotal role in anticancer immunity, and the potential applications of cDC1-based strategies in immunotherapy.
Topics: Humans; Dendritic Cells; Neoplasms; Immunotherapy; CD8-Positive T-Lymphocytes
PubMed: 37907944
DOI: 10.1186/s13062-023-00430-5