Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models
TL;DR: Evidence is provided that AFP-enriched DEXs can trigger potent antigen-specific antitumor immune responses and reshape the tumor microenvironment in HCC mice and thus provide a cell-free vaccine option for HCC immunotherapy.
About: This article is published in Journal of Hepatology.The article was published on 2017-10-01. It has received 238 citations till now. The article focuses on the topics: Tumor microenvironment & Immunotherapy.
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TL;DR: The fundamental processes of exosome formation and uptake are described and the physiological and pathological roles of exOSomes in biology are illustrated with a focus on how exosomes can be exploited or engineered as powerful tools in translational medicine.
Abstract: Exosomes are common membrane-bound nanovesicles that contain diverse biomolecules, such as lipids, proteins, and nucleic acids. Exosomes are derived from cells through exocytosis, are ingested by target cells, and can transfer biological signals between local or distant cells. Exosome secretion is a constitutive phenomenon that is involved in both physiological and pathological processes and determines both the exosomal surface molecules and the contents. Hence, we can exploit exosomes as biomarkers, vaccines and drug carriers and modify them rationally for therapeutic interventions. However, it is still a challenge to identify, isolate and quantify exosomes accurately, efficiently and selectively. Further studies on exosomes will explore their potential in translational medicine and provide new avenues for the creation of effective clinical diagnostics and therapeutic strategies; the use of exosomes in these applications can be called exosome theranostics. This review describes the fundamental processes of exosome formation and uptake. In addition, the physiological and pathological roles of exosomes in biology are also illustrated with a focus on how exosomes can be exploited or engineered as powerful tools in translational medicine.
626 citations
Cites background from "Dendritic cell-derived exosomes eli..."
...For instance, in three hepatocellular carcinoma mouse models with antigenic and pathological heterogeneity, exosomes that were derived from antigen-expressing DCs triggered strong antigen-specific immune responses, revealing a significant anti-tumor function and leading to prolonged survival rates [164]....
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TL;DR: The significance of exosomes in the occurrence, development, diagnosis and treatment of HCC is revealed to reveal, which in turn might help to further elucidate the mechanism of exOSomes in HCC, and promote the use ofExosomal substances in the clinical diagnosis and Treatment of H CC.
Abstract: Hepatocellular carcinoma (HCC) is the most commonmalignancy. Exsome plays a significant role in the elucidation of signal transduction pathways between hepatoma cells, angiogenesis and early diagnosis of HCC. Exosomes are small vesicular structures that mediate interaction between different types of cells, and contain a variety of components (including DNA, RNA, and proteins). Numerous studies have shown that these substances in exosomes are involved in growth, metastasis and angiogenesis in liver cancer, and then inhibited the growth of liver cancer by blocking the signaling pathway of liver cancer cells. In addition, the exosomal substances could also be used as markers for screening early liver cancer. In this review, we summarized to reveal the significance of exosomes in the occurrence, development, diagnosis and treatment of HCC, which in turn might help us to further elucidate the mechanism of exosomes in HCC, and promote the use of exosomes in the clinical diagnosis and treatment of HCC.
234 citations
Cites background from "Dendritic cell-derived exosomes eli..."
..., AFP-rich exosomes elicited a specific antitumor immune response, providing a new vaccine-free approach for treating HCC [97]....
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TL;DR: The recent progress on HCC immunology is provided from both basic and clinical perspectives, and potential advances and challenges of immunotherapy in HCC are discussed.
Abstract: Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it’s well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.
225 citations
TL;DR: This study demonstrates that an exosomal anchor peptide enables direct, effective functionalization and capture of exosomes, thus providing a tool for exosome engineering, probing gene function in vivo, and targeted therapeutic drug delivery.
Abstract: Exosomes are circulating nanovesicular carriers of macromolecules, increasingly used for diagnostics and therapeutics. The ability to load and target patient-derived exosomes without altering exosomal surfaces is key to unlocking their therapeutic potential. We demonstrate that a peptide (CP05) identified by phage display enables targeting, cargo loading, and capture of exosomes from diverse origins, including patient-derived exosomes, through binding to CD63-an exosomal surface protein. Systemic administration of exosomes loaded with CP05-modified, dystrophin splice-correcting phosphorodiamidate morpholino oligomer (EXOPMO) increased dystrophin protein 18-fold in quadriceps of dystrophin-deficient mdx mice compared to CP05-PMO. Loading CP05-muscle-targeting peptide on EXOPMO further increased dystrophin expression in muscle with functional improvement without any detectable toxicity. Our study demonstrates that an exosomal anchor peptide enables direct, effective functionalization and capture of exosomes, thus providing a tool for exosome engineering, probing gene function in vivo, and targeted therapeutic drug delivery.
213 citations
Cites background from "Dendritic cell-derived exosomes eli..."
...To assess the utility of exosomes captured through CP05, we isolated exosomes from serum from patients with HCC and pancreatic cancer and examined the expression of tumor-associated antigens such as -fetoprotein (AFP; HCC-specific antigen) (24) and glypican-1 (GPC1; pancreatic cancer–specific antigen) (25)....
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TL;DR: The role of exosomes in the regulation of tumor progression and the potential resistance mechanism to immunotherapy via exosomal PD-L1 are discussed and it is proposed that exosome PD- L1 may have the potential to be a target to overcome resistance to anti-PD-1/PD-L 1 antibody therapy.
Abstract: Programmed death ligand 1 (PD-L1), a type I transmembrane protein, binds to its receptor PD-1 to suppress the activation of T cells, thereby maintaining immunological homeostasis. In contrast, tumor cells highly express PD-L1, which binds to receptor PD-1 expressed on activated T cells, leading to immune escape. Anti-PD-1/PD-L1 immune checkpoint therapy blocks the binding of PD-1/PD-L1 to reinvigorate the exhausted T cells, thereby inhibiting tumor growth. Exosomes are biologically active lipid-bilayer nanovesicles secreted by various cell types that mediate intercellular signal communication. Numerous studies have shown that tumor cells are able to promote tumor epithelial-mesenchymal transition, angiogenesis, and immune escape by releasing exosomes. Recent studies imply that tumor-derived exosomes could carry PD-L1 in the same membrane topology as the cell surface, thereby resisting immune checkpoint therapy. In this review, we mainly discuss the role of exosomes in the regulation of tumor progression and the potential resistance mechanism to immunotherapy via exosomal PD-L1. In addition, we propose that exosomal PD-L1 may have the potential to be a target to overcome resistance to anti-PD-1/PD-L1 antibody therapy.
196 citations
References
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TL;DR: This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States.
2,733 citations
University of Gothenburg1, University of Melbourne2, University of California, San Diego3, Semmelweis University4, Cedars-Sinai Medical Center5, University of Oxford6, Pohang University of Science and Technology7, Agency for Science, Technology and Research8, La Trobe University9, Brown University10, Icahn School of Medicine at Mount Sinai11, Hiroshima University12, Utrecht University13, Johns Hopkins University14, French Institute of Health and Medical Research15
TL;DR: The International Society for Extracellular Vesicles (ISEV) provides researchers with a minimal set of biochemical, biophysical and functional standards that should be used to attribute any specific biological cargo or functions to EVs.
Abstract: Secreted membrane-enclosed vesicles, collectively called extracellular vesicles (EVs), which include exosomes, ectosomes, microvesicles, microparticles, apoptotic bodies and other EV subsets, encompass a very rapidly growing scientific field in biology and medicine. Importantly, it is currently technically challenging to obtain a totally pure EV fraction free from non-vesicular components for functional studies, and therefore there is a need to establish guidelines for analyses of these vesicles and reporting of scientific studies on EV biology. Here, the International Society for Extracellular Vesicles (ISEV) provides researchers with a minimal set of biochemical, biophysical and functional standards that should be used to attribute any specific biological cargo or functions to EVs.
2,028 citations
"Dendritic cell-derived exosomes eli..." refers background in this paper
...Exosomes are small extracellular vesicles with sizes of 30-100 nm (in diameter) secreted by a wide variety of cells [7, 8]....
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TL;DR: Dendritic cells are shown to secrete antigen presenting vesicles, called exosomes, which express functional Major Histocompatibility Complex class I and class II, and T-cell costimulatory molecules, which prime specific cytotoxic T lymphocytes in vivo.
Abstract: Dendritic cells (DCs) are professional antigen presenting cells with the unique capacity to induce primary and secondary immune responses in vivo. Here, we show that DCs secrete antigen presenting vesicles, called exosomes, which express functional Major Histocompatibility Complex class I and class II, and T-cell costimulatory molecules. Tumor peptide-pulsed DC-derived exosomes prime specific cytotoxic T lymphocytes in vivo and eradicate or suppress growth of established murine tumors in a T cell-dependent manner. Exosome-based cell-free vaccines represent an alternative to DC adoptive therapy for suppressing tumor growth.
2,012 citations
"Dendritic cell-derived exosomes eli..." refers background in this paper
...mastocytoma and mammary carcinoma mice [10], showing that DEXs can replace DCs as effective vaccines....
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TL;DR: The first exosome Phase I trial highlighted the feasibility of large scale exosomal MHC class II molecules production and the safety of exosomes administration.
Abstract: BACKGROUND: DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients Secondary endpoints were the monitoring of T cell responses and the clinical outcome PATIENTS AND METHODS: Exosomes were purified from day 7 autologous monocyte derived-DC cultures Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen) were enrolled from 2000 to 2002 and received four exosome vaccinations Two dose levels of either MHC class II molecules (013 versus 040 x 1014 molecules) or peptides (10 versus 100 mug/ml) were tested Evaluations were performed before and 2 weeks after immunization A continuation treatment was performed in 4 cases of non progression RESULTS: The GMP process allowed to harvest about 5 x 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients There was no grade II toxicity and the maximal tolerated dose was not achieved One patient exhibited a partial response according to the RECIST criteria This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood CONCLUSION: The first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration
1,029 citations
"Dendritic cell-derived exosomes eli..." refers background in this paper
...Importantly, recent clinical trials on advanced melanoma patients with DEXs have demonstrated encouraging results, highlighting DEXs’ applicability [13]....
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...There is growing evidence showing that DEX activates natural killer (NK) cells [13, 25]....
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TL;DR: Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC, and some patients experienced long term stability of disease and activation of immune effectors.
Abstract: There is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC). This Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals. Thirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1–2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52–665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4. Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effectors
899 citations
"Dendritic cell-derived exosomes eli..." refers methods in this paper
...This concept was adopted in other tumor models [11, 12]....
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