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Cell Jan 2024Immune checkpoint inhibition treatment using aPD-1 monoclonal antibodies is a promising cancer immunotherapy approach. However, its effect on tumor immunity is narrow,...
Immune checkpoint inhibition treatment using aPD-1 monoclonal antibodies is a promising cancer immunotherapy approach. However, its effect on tumor immunity is narrow, as most patients do not respond to the treatment or suffer from recurrence. We show that the crosstalk between conventional type I dendritic cells (cDC1) and T cells is essential for an effective aPD-1-mediated anti-tumor response. Accordingly, we developed a bispecific DC-T cell engager (BiCE), a reagent that facilitates physical interactions between PD-1 T cells and cDC1. BiCE treatment promotes the formation of active dendritic/T cell crosstalk in the tumor and tumor-draining lymph nodes. In vivo, single-cell and physical interacting cell analysis demonstrates the distinct and superior immune reprogramming of the tumors and tumor-draining lymph nodes treated with BiCE as compared to conventional aPD-1 treatment. By bridging immune cells, BiCE potentiates cell circuits and communication pathways needed for effective anti-tumor immunity.
Topics: Humans; Antibodies, Bispecific; Dendritic Cells; Immunotherapy; Neoplasms; T-Lymphocytes
PubMed: 38242085
DOI: 10.1016/j.cell.2023.12.011 -
Immunity Aug 2023Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have...
Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have been intensively investigated but are still not fully understood as their phenotypes, especially in the DC2 lineage and the recently described human DC3s, overlap with monocytes. Here, using LEGENDScreen to profile DC vs. monocyte lineages, we found sustained expression of FLT3 and CD45RB through the whole DC lineage, allowing DCs and their precursors to be distinguished from monocytes. Using fate mapping models, single-cell RNA sequencing and adoptive transfer, we identified a lineage of murine CD16/32CD172a DC3, distinct from DC2, arising from Ly6C monocyte-DC progenitors (MDPs) through Lyz2Ly6CCD11c pro-DC3s, whereas DC2s develop from common DC progenitors (CDPs) through CD7Ly6CCD11c pre-DC2s. Corresponding DC subsets, developmental stages, and lineages exist in humans. These findings reveal DC3 as a DC lineage phenotypically related to but developmentally different from monocytes and DC2s.
Topics: Mice; Humans; Animals; Monocytes; Stem Cells; Phenotype; Cells, Cultured; Dendritic Cells; Cell Differentiation
PubMed: 37506694
DOI: 10.1016/j.immuni.2023.07.001 -
Nature Aug 2023Cancer cells evade T cell-mediated killing through tumour-immune interactions whose mechanisms are not well understood. Dendritic cells (DCs), especially type-1...
Cancer cells evade T cell-mediated killing through tumour-immune interactions whose mechanisms are not well understood. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours. DC functions are orchestrated by pattern recognition receptors, although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity, but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour-cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8 T cell immunity, and overcomes therapeutic resistance to checkpoint blockade and T cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1s compete for glutamine uptake via the transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid in promoting cDC1 function. Further, glutamine signalling via FLCN impinges on TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner and phenocopies SLC38A2 deficiency by eliminating the anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1s that underpins tumour immune evasion, and reveal glutamine acquisition and signalling in cDC1s as limiting events for DC activation and putative targets for cancer treatment.
Topics: Amino Acid Transport System A; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; CD8-Positive T-Lymphocytes; Dendritic Cells; Glutamine; Neoplasms; Proto-Oncogene Proteins; Signal Transduction; Tumor Suppressor Proteins
PubMed: 37407815
DOI: 10.1038/s41586-023-06299-8 -
Science Immunology Jul 2023Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional...
Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8 T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8 T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.
Topics: Humans; Mice; Animals; CD8-Positive T-Lymphocytes; Cellular Reprogramming; Dendritic Cells; Antigens, Neoplasm; Melanoma
PubMed: 37418548
DOI: 10.1126/sciimmunol.add4817 -
Nature Nanotechnology Nov 2023Effective cancer immunotherapy is usually blocked by immunosuppressive factors in the tumour microenvironment, resulting in tumour promotion, metastasis and recurrence....
Effective cancer immunotherapy is usually blocked by immunosuppressive factors in the tumour microenvironment, resulting in tumour promotion, metastasis and recurrence. Here we combine lipid nanoparticle-mRNA formulations and dendritic cell therapy (named CATCH) to boost the cancer-immunity cycle via progressive steps to overcome the immunosuppressive tumour microenvironment. Multiple types of sugar-alcohol-derived lipid nanoparticles are conceived to modulate the cancer-immunity cycle. First, one type of lipid nanoparticle containing CD40 ligand mRNA induces robust immunogenic cell death in tumoural tissues, leading to the release of tumour-associated antigens and the expression of CD40 ligand. Next, dendritic cells engineered by another type of lipid nanoparticle encapsulating CD40 mRNA are adoptively transferred, which are then activated by the CD40 ligand molecules in tumoural tissues. This promotes the secretion of multiple cytokines and chemokines, and the upregulation of co-stimulatory molecules on dendritic cells, which are crucial for reprogramming the tumour microenvironment and priming the T-cell responses. After dendritic cells present tumour-associated antigens to T cells, all the above stepwise events contribute to boosting a potent tumour-specific T-cell immunity that eradicates established tumours, suppresses distal lesions and prevents tumour rechallenge.
Topics: Humans; CD40 Ligand; RNA, Messenger; Dendritic Cells; Neoplasms; Tumor Microenvironment
PubMed: 37500773
DOI: 10.1038/s41565-023-01453-9 -
Immunity Oct 2023In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally... (Review)
Review
In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses. Here, we review the current understanding of DC-T cell interactions at both priming and effector sites of immune responses. We place emerging insights into DC functions in tumor immunity in the context of DC development, ontogeny, and functions in other settings and propose that DCs control at least two T cell-associated checkpoints of the cancer immunity cycle. Our understanding of both checkpoints has implications for the development of new approaches to cancer immunotherapy.
Topics: Animals; Humans; Cell Communication; Cell Differentiation; Dendritic Cells; Immune Tolerance; Immunotherapy; Neoplasms; T-Lymphocytes
PubMed: 37708889
DOI: 10.1016/j.immuni.2023.08.014 -
Cancer Cell Aug 2023Type 1 conventional dendritic cells (cDC1) can support T cell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is...
Type 1 conventional dendritic cells (cDC1) can support T cell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is poorly understood. Here, we use imaging-based deep learning to identify intratumoral cDC1-CD8 T cell clustering as a unique feature of protective anti-cancer immunity. These clusters form selectively in stromal tumor regions and constitute niches in which cDC1 activate TCF1 stem-like CD8 T cells. We identify a distinct population of immunostimulatory CCR7 cDC1 that produce CXCL9 to promote cluster formation and cross-present tumor antigens within these niches, which is required for intratumoral CD8 T cell differentiation and expansion and promotes cancer immune control. Similarly, in human cancers, CCR7 cDC1 interact with CD8 T cells in clusters and are associated with patient survival. Our findings reveal an intratumoral phase of the anti-cancer T cell response orchestrated by tumor-residing cDC1 that determines protective versus ineffective immunity and could be exploited for cancer therapy.
Topics: Humans; CD8-Positive T-Lymphocytes; Receptors, CCR7; Neoplasms; Antigens, Neoplasm; Dendritic Cells
PubMed: 37451271
DOI: 10.1016/j.ccell.2023.06.008 -
Immunological Reviews Aug 2023Dendritic cells (DCs) are innate immune cells that detect and process environmental signals and communicate them with T cells to bridge innate and adaptive immunity.... (Review)
Review
Dendritic cells (DCs) are innate immune cells that detect and process environmental signals and communicate them with T cells to bridge innate and adaptive immunity. Immune signals and microenvironmental cues shape the function of DC subsets in different contexts, which is associated with reprogramming of cellular metabolic pathways. In addition to integrating these extracellular cues to meet bioenergetic and biosynthetic demands, cellular metabolism interplays with immune signaling to shape DC-dependent immune responses. Emerging evidence indicates that lipid metabolism serves as a key regulator of DC responses. Here, we summarize the roles of fatty acid and cholesterol metabolism, as well as selective metabolites, in orchestrating the functions of DCs. Specifically, we highlight how different lipid metabolic programs, including de novo fatty acid synthesis, fatty acid β oxidation, lipid storage, and cholesterol efflux, influence DC function in different contexts. Further, we discuss how dysregulation of lipid metabolism shapes DC intracellular signaling and contributes to the impaired DC function in the tumor microenvironment. Finally, we conclude with a discussion on key future directions for the regulation of DC biology by lipid metabolism. Insights into the connections between lipid metabolism and DC functional specialization may facilitate the development of new therapeutic strategies for human diseases.
Topics: Humans; Lipid Metabolism; Dendritic Cells; Fatty Acids; Cholesterol; Biology
PubMed: 37172120
DOI: 10.1111/imr.13215 -
Cell Reports Jul 2023Tissue-resident macrophages (TRMs) and dendritic cells (DCs) are highly heterogeneous and essential for immunity, tissue regeneration, and homeostasis maintenance. Here,...
Tissue-resident macrophages (TRMs) and dendritic cells (DCs) are highly heterogeneous and essential for immunity, tissue regeneration, and homeostasis maintenance. Here, we comprehensively profile the heterogeneity of TRMs and DCs across adult zebrafish organs via single-cell RNA sequencing. We identify two macrophage subsets: pro-inflammatory macrophages with potent phagocytosis signatures and pro-remodeling macrophages with tissue regeneration signatures in barrier tissues, liver, and heart. In parallel, one conventional dendritic cell (cDC) population with prominent antigen presentation capacity and plasmacytoid dendritic cells (pDCs) featured by anti-virus properties are also observed in these organs. Remarkably, in addition to a single macrophage/microglia population with potent phagocytosis capacity, a pDC population and two distinct cDC populations are identified in the brain. Finally, we generate specific reporter lines for in vivo tracking of macrophage and DC subsets. Our study depicts the landscape of TRMs and DCs and creates valuable tools for in-depth study of these cells in zebrafish.
Topics: Animals; Zebrafish; Macrophages; Gene Expression Profiling; Dendritic Cells; Phagocytosis; Transcriptome
PubMed: 37453064
DOI: 10.1016/j.celrep.2023.112793 -
European Journal of Immunology Nov 2023This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis...
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. This article provides protocols with top ticks and pitfalls for preparation and successful generation of mouse and human DC from different cellular sources, such as murine BM and HoxB8 cells, as well as human CD34 cells from cord blood, BM, and peripheral blood or peripheral blood monocytes. We describe murine cDC1, cDC2, and pDC generation with Flt3L and the generation of BM-derived DC with GM-CSF. Protocols for human DC generation focus on CD34 cell culture on OP9 cell layers for cDC1, cDC2, cDC3, and pDC subset generation and DC generation from peripheral blood monocytes (MoDC). Additional protocols include enrichment of murine DC subsets, CRISPR/Cas9 editing, and clinical grade human DC generation. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
Topics: Animals; Mice; Humans; Dendritic Cells; Monocytes; Antigens, CD34; Phenotype; Cell Differentiation
PubMed: 36303448
DOI: 10.1002/eji.202249816