Anti-CTLA-4 antibody-functionalized dendritic cell-derived exosomes targeting tumor-draining lymph nodes for effective induction of antitumor T-cell responses

Phung, Cao Dai; Pham, Tung Thanh; Nguyen, Hanh Thuy; Ou, Wenquan; Jeong, Jee–Heon; Choi, Han‐Gon; Ku, Sae Kwang; Yong, Chul Soon; Kim, Jong Oh

doi:10.1016/j.actbio.2020.08.008

Cited by 79 publications

(59 citation statements)

References 45 publications

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“…58 59 As other important cellular immune-response markers, the levels of IFN-γ and TNF-α, which are associated with the activation of T cells, were measured to confirm the improvement of T-cell activity toward the tumor. 60 As expected, CHA-SME promoted IFN-γ production in peripheral blood and spleens (online supplemental figure S9B,C). It was also noted that CHA-SME treatment led to substantially higher secreted levels of both IFN-γ and TNF-α in tumor tissues as compared with the control group (online supplemental figure S9D, H and K), confirming increased activation and infiltration of T cells into the tumor.…”

Section: Open Accesssupporting

confidence: 75%

“…In addition to the increased proportion of tumorinfiltrating T cells, another important characteristic of effective cancer immunotherapies is the memory feature, which confers a long-term antitumor response primarily based on the activity of memory T cells. 60 The generation of memory T cells plays a critical role in the rapid clearance and neutralization of pathogens encountered previously by the immune system. 63 Memory T cells can be typically classified into two subsets, T CM and T EM , based on the phenotypic markers, functional attributes, and migratory properties.…”

Section: Open Accessmentioning

confidence: 99%

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Oral SMEDDS promotes lymphatic transport and mesenteric lymph nodes target of chlorogenic acid for effective T-cell antitumor immunity

Gao

et al. 2021

J Immunother Cancer

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BackgroundMesenteric lymph nodes (MLNs) are critical draining lymph nodes of the immune system that accommodate more than half of the body’s lymphocytes, suggesting their potential value as a cancer immunotherapy target. Therefore, efficient delivery of immunomodulators to the MLNs holds great potential for activating immune responses and enhancing the efficacy of antitumor immunotherapy. Self-microemulsifying drug delivery systems (SMEDDS) have attracted increasing attention to improving oral bioavailability by taking advantage of the intestinal lymphatic transport pathway. Relatively little focus has been given to the lymphatic transport advantage of SMEDDS for efficient immunomodulators delivery to the MLNs. In the present study, we aimed to change the intestinal lymphatic transport paradigm from increasing bioavailability to delivering high concentrations of immunomodulators to the MLNs.MethodsChlorogenic acid (CHA)-encapsulated SMEDDS (CHA-SME) were developed for targeted delivery of CHA to the MLNs. The intestinal lymphatic transport, immunoregulatory effects on immune cells, and overall antitumor immune efficacy of CHA-SME were investigated through in vitro and in vivo experiments.ResultsCHA-SME enhanced drug permeation through intestinal epithelial cells and promoted drug accumulation within the MLNs via the lymphatic transport pathway. Furthermore, CHA-SME inhibited tumor growth in subcutaneous and orthotopic glioma models by promoting dendritic cell maturation, priming the naive T cells into effector T cells, and inhibiting the immunosuppressive component. Notably, CHA-SME induced a long-term immune memory effect for immunotherapy.ConclusionsThese findings indicate that CHA-SME have great potential to enhance the immunotherapeutic efficacy of CHA by activating antitumor immune responses.

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Section: Open Accesssupporting

confidence: 75%

Section: Open Accessmentioning

confidence: 99%

Oral SMEDDS promotes lymphatic transport and mesenteric lymph nodes target of chlorogenic acid for effective T-cell antitumor immunity

Gao

et al. 2021

J Immunother Cancer

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“…For example, immature dendritic cells (imDCs) can produce exosomes, but they could not target tumor selectively, when they were engineered to express a special exosomal membrane protein called Lamp2b , they could deliver cargo of DOX to tumor selectively and inhibit their growth without obvious cardiotoxicity, which is of great potential for clinical application 74 . Recently, Phung et al developed an anti-cancer strategy based on DC-derived exosomes: anti-CTLA-4 antibody was anchored in lipids of exosomes of DCs, which guide the exosomes towards T cells, in addition, they endowed the exosomes with ability to block checkpoint, both enhancing the T cell response to cancer cells synergistically 75 . Stimulating cancer-specific T cells to response is expected to become a replacement strategy for cancer vaccine and can also decrease the usage of DOX, thus ameliorating cardiotoxicity.…”

Section: Exosomes As Therapeutic Delivery Vehiclesmentioning

confidence: 99%

Potential of exosomes as diagnostic biomarkers and therapeutic carriers for doxorubicin-induced cardiotoxicity

et al. 2021

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Doxorubicin (DOX) is a kind of representative anthracyclines. It has greatly prolonged lifespan of cancer patients. However, a long course of DOX chemotherapy could induce various forms of deaths of cardiomyocytes, such as apoptosis, pyroptosis and ferroptosis, contributing to varieties of cardiac complications called cardiotoxicity. It has become a major concern considering the large number of cancer patients' worldwide and increased survival rates after chemotherapy. Exosomes, a subgroup of extracellular vesicles (EVs), are secreted by nearly all cells and consist of lipid bilayers, nucleic acids and proteins. They can serve as mediators between intercellular communication via the transfer of bioactive molecules from secretory to recipient cells, modulating multiple pathophysiological processes. It has been proven that exosomes in body fluids can serve as biomarkers for doxorubicin-induced cardiotoxicity (DIC). Moreover, exosomes have attracted considerable attention because of their capacity as carriers of certain proteins, genetic materials (miRNA and lncRNA), and chemotherapeutic drugs to decrease the dosage of DOX and alleviate cardiotoxicity. This review briefly describes the characteristics of exosomes and highlights their clinical application potential as diagnostic biomarkers and drug delivery vehicles for DIC, thus providing a strategy for addressing it based on exosomes.

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“…( 2 ) Scheme of EVs-mediated T-cell activation and ( b ) data analysis of CD69, a T-cell activation marker on CD4+ and CD8+ T cells following incubation with different exosomes formulations. Reproduced from [ 109 ] with permission of Elsevier. * p < 0.05, ** p < 0.01, *** p < 0.001, one-way ANOVA analysis.…”

Section: Figurementioning

confidence: 99%

Extracellular Vesicles and Their Current Role in Cancer Immunotherapy

Giacobino

Canta

Fornaguera

et al. 2021

Cancers

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Extracellular vesicles (EVs) are natural particles formed by the lipid bilayer and released from almost all cell types to the extracellular environment both under physiological conditions and in presence of a disease. EVs are involved in many biological processes including intercellular communication, acting as natural carriers in the transfer of various biomolecules such as DNA, various RNA types, proteins and different phospholipids. Thanks to their transfer and targeting abilities, they can be employed in drug and gene delivery and have been proposed for the treatment of different diseases, including cancer. Recently, the use of EVs as biological carriers has also been extended to cancer immunotherapy. This new technique of cancer treatment involves the use of EVs to transport molecules capable of triggering an immune response to damage cancer cells. Several studies have analyzed the possibility of using EVs in new cancer vaccines, which represent a particular form of immunotherapy. In the literature there are only few publications that systematically group and collectively discuss these studies. Therefore, the purpose of this review is to illustrate and give a partial reorganization to what has been produced in the literature so far. We provide basic notions on cancer immunotherapy and describe some clinical trials in which therapeutic cancer vaccines are tested. We thus focus attention on the potential of EV-based therapeutic vaccines in the treatment of cancer patients, overviewing the clinically relevant trials, completed or still in progress, which open up new perspectives in the fight against cancer.

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Anti-CTLA-4 antibody-functionalized dendritic cell-derived exosomes targeting tumor-draining lymph nodes for effective induction of antitumor T-cell responses

Cited by 79 publications

References 45 publications

Oral SMEDDS promotes lymphatic transport and mesenteric lymph nodes target of chlorogenic acid for effective T-cell antitumor immunity

Oral SMEDDS promotes lymphatic transport and mesenteric lymph nodes target of chlorogenic acid for effective T-cell antitumor immunity

Potential of exosomes as diagnostic biomarkers and therapeutic carriers for doxorubicin-induced cardiotoxicity

Extracellular Vesicles and Their Current Role in Cancer Immunotherapy

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