RESUMEN
The development of artificial Antigen Presenting Cells (aAPCs) has led to improvements in adoptive T cell therapy (ACT), an immunotherapy, for cancer treatment. aAPCs help to streamline the consistent production and expansion of T cells, thus reducing the time and costs associated with ACT. However, several issues still exist with ACT, such as insufficient T cell potency, which diminishes the translational potential for ACT. While aAPCs have been used primarily to increase production efficiency of T cells for ACT, the intrinsic properties of a biomaterial-based aAPC may affect T cell phenotype and function. In CD8+ T cells, reactive oxygen species (ROS) and oxidative stress accumulation can activate Forkhead box protein O1 (FOXO1) to transcribe antioxidants which reduce ROS and improve memory formation. Alginate, a biocompatible and antioxidant rich biomaterial, is promising for incorporation into an aAPC formulation to modulate T cell phenotype. To investigate its utility, a novel alginate-based aAPC platform was developed that preferentially expanded CD8+ T cells with memory related features. Alginate-based aAPCs allowed for greater control of CD8+ T cell qualities, including, significantly improved in vivo persistence and augmented in vivo anti-tumor T cell responses.
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Alginatos , Células Presentadoras de Antígenos , Linfocitos T CD8-positivos , Memoria Inmunológica , Inmunoterapia Adoptiva , Alginatos/química , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Animales , Inmunoterapia Adoptiva/métodos , Células Presentadoras de Antígenos/inmunología , Memoria Inmunológica/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones , Especies Reactivas de Oxígeno/metabolismo , Humanos , Proliferación Celular/efectos de los fármacosRESUMEN
Trogocytosis, an active cellular process involving the transfer of plasma membrane and attached cytosol during cell-to-cell contact, has been observed prominently in CD4 T cells interacting with antigen-presenting cells carrying antigen-loaded major histocompatibility complex (MHC) class II molecules. Despite the inherent absence of MHC class II molecules in CD4 T cells, they actively acquire these molecules from encountered antigen-presenting cells, leading to the formation of antigen-loaded MHC class II molecules-dressed CD4 T cells. Subsequently, these dressed CD4 T cells engage in antigen presentation to other CD4 T cells, revealing a dynamic mechanism of immune communication. The transferred membrane proteins through trogocytosis retain their surface localization, thereby altering cellular functions. Concurrently, the donor cells experience a loss of membrane proteins, resulting in functional changes due to the altered membrane properties. This chapter provides a focused exploration into trogocytosis-mediated transfer of immune regulatory molecules and its consequential impact on diverse immune responses.
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Células Presentadoras de Antígenos , Linfocitos T CD4-Positivos , Trogocitosis , Humanos , Animales , Comunicación Celular , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Presentadoras de Antígenos/citología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismoRESUMEN
Introduction: Adjuvants added to subunit vaccines augment antigen-specific immune responses. One mechanism of adjuvant action is activation of pattern recognition receptors (PRRs) on innate immune cells. Bordetella colonization factor A (BcfA); an outer membrane protein with adjuvant function, activates TH1/TH17-polarized immune responses to protein antigens from Bordetella pertussis and SARS CoV-2. Unlike other adjuvants, BcfA does not elicit a TH2 response. Methods: To understand the mechanism of BcfA-driven TH1/TH17 vs. TH2 activation, we screened PRRs to identify pathways activated by BcfA. We then tested the role of this receptor in the BcfA-mediated activation of bone marrow-derived dendritic cells (BMDCs) using mice with germline deletion of TLR4 to quantify upregulation of costimulatory molecule expression and cytokine production in vitro and in vivo. Activity was also tested on human PBMCs. Results: PRR screening showed that BcfA activates antigen presenting cells through murine TLR4. BcfA-treated WT BMDCs upregulated expression of the costimulatory molecules CD40, CD80, and CD86 and produced IL-6, IL-12/23 p40, and TNF-α while TLR4 KO BMDCs were not activated. Furthermore, human PBMCs stimulated with BcfA produced IL-6. BcfA-stimulated murine BMDCs also exhibited increased uptake of the antigen DQ-OVA, supporting a role for BcfA in improving antigen presentation to T cells. BcfA further activated APCs in murine lungs. Using an in vitro TH cell polarization system, we found that BcfA-stimulated BMDC supernatant supported TFH and TH1 while suppressing TH2 gene programming. Conclusions: Overall, these data provide mechanistic understanding of how this novel adjuvant activates immune responses.
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Adyuvantes Inmunológicos , Células TH1 , Células Th2 , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , Ratones , Células TH1/inmunología , Células Th2/inmunología , Adyuvantes Inmunológicos/farmacología , Humanos , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Ratones Noqueados , Células Dendríticas/inmunología , Ratones Endogámicos C57BL , Células T Auxiliares Foliculares/inmunología , Citocinas/metabolismo , Activación de Linfocitos/inmunologíaRESUMEN
Mechanical force has repeatedly been highlighted to be involved in T cell activation. However, the biological significance of mechanical force for T cell receptor signaling remains under active consideration. Here, guided by theoretical analysis, we provide a perspective on how mechanical forces between a T cell and an antigen-presenting cell can influence the bond of a single T cell receptor major histocompatibility complex during early T cell activation. We point out that the lifetime of T cell receptor bonds and thus the degree of their phosphorylation which is essential for T cell activation depends considerably on the T cell receptor rigidity and the average magnitude and frequency of an applied oscillatory force. Such forces could be, for example, produced by protrusions like microvilli during early T cell activation or invadosomes during full T cell activation. These features are suggestive of mechanical force being exploited by T cells to advance self-nonself discrimination in early T cell activation.
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Activación de Linfocitos , Receptores de Antígenos de Linfocitos T , Linfocitos T , Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Humanos , Animales , Fosforilación , Transducción de Señal/inmunología , Fenómenos Biomecánicos , Células Presentadoras de Antígenos/inmunologíaRESUMEN
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a deadly pulmonary disease with impaired immunological response that causes significant tissue damage and organ failure. Postmortem examination of the lung is a useful tool for understanding the immunopathogenesis of this virus. Lung autopsy samples from seven dead SARS-CoV-2 patients were obtained and evaluated using hematoxylin and eosin stain to analyze the histopathological changes in those samples, on the other hand, Immunohistochemical (IHC) staining was used for detection of CD21, CD1a, CR1 (CD35), CD68, Myeloperoxidase (MPO), CD15, CD56, CD3, CD20, CD4, and CD8 cells markers. Histopathological examination revealed diffuse alveolar damage with extensive parenchymal architecture distortion, intravascular fibrin clot, deposition of collagen fibers, vascular congestions and blood vessels containing thrombi, pneumocyte type II with inflammatory cell infiltration. The IHC staining for the innate immune cells such as antigen-presenting cells (APCs) including dendritic cells, Macrophages, and neutrophils showed a strong positive staining, while CD56 Natural killer (NK) cells showed negative staining. On the other hand, the specific immune cells including; CD20 B cells, CD3 T cells, and CD4 helper T cells, showed positive staining while CD8 Cytotoxic T cells showed negative staining. The lung autopsy samples from patients with COVID-19 confirmed the presence of APCs through the positive staining of CD21, CD1a, CD35, CD68, MPO, and CD15 expressed the virus recognition, proinflammatory cytokine production, and adaptive immune cells activation through CD3, CD4, and CD20 positive staining and the role of APCs in the severity of pulmonary infection and pathogenesis of SARS-CoV-2 infection however the absence of the CD56 NK and CD8 cytotoxic T explains the worse infection status for the patients.
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Células Presentadoras de Antígenos , Autopsia , COVID-19 , Pulmón , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/patología , Pulmón/patología , Pulmón/inmunología , Pulmón/virología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , SARS-CoV-2/inmunología , Masculino , Persona de Mediana Edad , Femenino , Anciano , Inmunohistoquímica , Adulto , Antígenos CD/metabolismoRESUMEN
Adoptive cell therapy (ACT) achieves substantial efficacy in the treatment of hematological malignancies and solid tumours, while enormous endeavors have been made to reduce relapse and extend the remission duration after ACT. For the genetically engineered T cells, their functionality and long-term anti-tumour potential depend on the specificity of the T cell receptor (TCR) or chimeric antigen receptor (CAR). In addition, the therapeutic benefit is directly to sufficient activation and proliferation of engineered T cells. Artificial antigen-presenting cells (aAPCs), as powerful boosters for ACT, have been applied to provide sustained stimulation of the cognate antigen and facilitate the expansion of sufficient T cells for infusion. In this review, we summarize the aAPCs used to generate effector cells for ACT and underline the mechanism by which aAPCs enhance the functionality of the effector cells. The manuscript includes investigations ranging from basic research to clinical trials, which we hope will highlight the importance of aAPCs and provide guidance for novel strategies to improve the effectiveness of ACT.
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Células Presentadoras de Antígenos , Inmunoterapia Adoptiva , Humanos , Células Presentadoras de Antígenos/inmunología , Inmunoterapia Adoptiva/métodos , Animales , Linfocitos T/inmunología , Linfocitos T/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
CD8 T cells are the predominant effector cells of adaptive immunity in preventing cytomegalovirus (CMV) multiple-organ disease caused by cytopathogenic tissue infection. The mechanism by which CMV-specific, naïve CD8 T cells become primed and clonally expand is of fundamental importance for our understanding of CMV immune control. For CD8 T-cell priming, two pathways have been identified: direct antigen presentation by infected professional antigen-presenting cells (pAPCs) and antigen cross-presentation by uninfected pAPCs that take up antigenic material derived from infected tissue cells. Studies in mouse models using murine CMV (mCMV) and precluding either pathway genetically or experimentally have shown that, in principle, both pathways can congruently generate the mouse MHC/H-2 class-I-determined epitope-specificity repertoire of the CD8 T-cell response. Recent studies, however, have shown that direct antigen presentation is the canonical pathway when both are accessible. This raised the question of why antigen cross-presentation is ineffective even under conditions of high virus replication thought to provide high amounts of antigenic material for feeding cross-presenting pAPCs. As delivery of antigenic material for cross-presentation is associated with programmed cell death, and as CMVs encode inhibitors of different cell death pathways, we pursued the idea that these inhibitors restrict antigen delivery and thus CD8 T-cell priming by cross-presentation. To test this hypothesis, we compared the CD8 T-cell responses to recombinant mCMVs lacking expression of the apoptosis-inhibiting protein M36 or the necroptosis-inhibiting protein M45 with responses to wild-type mCMV and revertant viruses expressing the respective cell death inhibitors. The data reveal that increased programmed cell death improves CD8 T-cell priming in mice capable of antigen cross-presentation but not in a mutant mouse strain unable to cross-present. These findings strongly support the conclusion that CMV cell death inhibitors restrict the priming of CD8 T cells by antigen cross-presentation.
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Presentación de Antígeno , Linfocitos T CD8-positivos , Reactividad Cruzada , Infecciones por Citomegalovirus , Animales , Linfocitos T CD8-positivos/inmunología , Ratones , Reactividad Cruzada/inmunología , Presentación de Antígeno/inmunología , Infecciones por Citomegalovirus/inmunología , Muromegalovirus/inmunología , Apoptosis , Citomegalovirus/inmunología , Células Presentadoras de Antígenos/inmunología , Ratones Endogámicos C57BL , Antígenos Virales/inmunologíaRESUMEN
BACKGROUND: Current needle-based vaccination for respiratory viruses is ineffective at producing sufficient, long-lasting local immunity in the elderly. Direct pulmonary delivery to the resident local pulmonary immune cells can create long-term mucosal responses. However, criteria for drug vehicle design rules that can overcome age-specific changes in immune cell functions have yet to be established. RESULTS: Here, in vivo charge-based nanoparticle (NP) uptake was compared in mice of two age groups (2- and 16-months) within the four notable pulmonary antigen presenting cell (APC) populations: alveolar macrophages (AM), interstitial macrophages (IM), CD103+ dendritic cells (DCs), and CD11b+ DCs. Both macrophage populations exhibited preferential uptake of anionic nanoparticles but showed inverse rates of phagocytosis between the AM and IM populations across age. DC populations demonstrated preferential uptake of cationic nanoparticles, which remarkably did not significantly change in the aged group. Further characterization of cell phenotypes post-NP internalization demonstrated unique surface marker expression and activation levels for each APC population, showcasing heightened DC inflammatory response to NP delivery in the aged group. CONCLUSION: The age of mice demonstrated significant preferences in the charge-based NP uptake in APCs that differed greatly between macrophages and DCs. Carefully balance of the targeting and activation of specific types of pulmonary APCs will be critical to produce efficient, age-based vaccines for the growing elderly population.
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Células Presentadoras de Antígenos , Células Dendríticas , Pulmón , Ratones Endogámicos C57BL , Nanopartículas , Fagocitosis , Animales , Nanopartículas/química , Ratones , Pulmón/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Presentadoras de Antígenos/inmunología , Macrófagos Alveolares/metabolismo , Polietilenglicoles/química , Envejecimiento , Femenino , Factores de EdadRESUMEN
Effective activation of an antigen-specific immune response hinges upon the intracellular delivery of cancer antigens to antigen-presenting cells (APCs), marking the initial stride in cancer vaccine development. Leveraging biomimetic topological morphology, we employed virus-like mesoporous silica nanoparticles (VMSNs) coloaded with antigens and toll-like receptor 9 (TLR9) agonists to craft a potent cancer vaccine. Our VMSNs could be efficiently internalized by APCs to a greater extent than their nonviral structured counterparts, thereby promoting the activation of APCs by upregulating the TLR9 pathway and cross-presenting ovalbumin (OVA) epitopes. In in vivo animal study, VMSN-based nanovaccines triggered substantial CD4+ and CD8+ lymphocyte populations in both lymph nodes and spleen while inducing the effector memory of adaptive T cells. Consequently, VMSN-based nanovaccines suppressed tumor progression and increased the survival rate of B16-OVA-bearing mice in both prophylactic and therapeutic studies. The combination of immune checkpoint blockade (ICB) with the VMSN-based nanovaccine has synergistic effects in significantly preventing tumor progression under therapeutic conditions. These findings highlight the potential of viral structure-mimicking mesoporous silica nanoparticles as promising candidates for antigen-delivering nanocarriers in vaccine development.
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Ratones Endogámicos C57BL , Nanopartículas , Dióxido de Silicio , Dióxido de Silicio/química , Animales , Nanopartículas/química , Ratones , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/química , Ovalbúmina/química , Ovalbúmina/inmunología , Porosidad , Inmunidad Adaptativa/efectos de los fármacos , Humanos , Células Presentadoras de Antígenos/inmunología , Neoplasias/inmunología , Femenino , Receptor Toll-Like 9/inmunología , Receptor Toll-Like 9/agonistas , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/química , Línea Celular TumoralRESUMEN
Precisely co-delivering antigens and immunosuppressants via nano/microcarriers to antigen-presenting cells (APCs) to induce antigen-specific immune tolerance represents a highly promising strategy for treating or preventing autoimmune diseases. The physicochemical properties of nano/microcarriers play a pivotal role in regulating immune function, with particle size and surface charge emerging as crucial parameters. In particular, very few studies have investigated micron-scale carriers of antigens. Herein, various nanoparticles and microparticles (NPs/MPs) with diverse particle sizes (ranging from 200 nm to 5 µm) and surface charges were prepared. Antigen peptides (MOG35-55) and immunosuppressants were encapsulated in these particles to induce antigen-specific immune tolerance. Two emulsifiers, PVA and PEMA, were employed to confer different surface charges to the NPs/MPs. The in vitro and in vivo studies demonstrated that NP/MP-PEMA could induce immune tolerance earlier than NP/MP-PVA and that NP/MP-PVA could induce immune tolerance more slowly and sustainably, indicating that highly negatively charged particles can induce immune tolerance more rapidly. Among the different sizes and charged particles tested, 200-nm-NP-PVA and 3-µm-MP-PEMA induced the greatest immune tolerance. In addition, the combination of NPs with MPs can further improve the induction of immune tolerance. In particular, combining 200 nm-NP-PVA with 3 µm-MP-PEMA or combining 500 nm-NP-PEMA with 3 µm-MP-PVA had optimal therapeutic efficacy. This study offers a new perspective for treating diseases by combining NPs with MPs and applying different emulsifiers to prepare NPs and MPs.
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Tolerancia Inmunológica , Ratones Endogámicos C57BL , Nanopartículas , Tamaño de la Partícula , Animales , Tolerancia Inmunológica/efectos de los fármacos , Nanopartículas/química , Nanopartículas/administración & dosificación , Inmunosupresores/administración & dosificación , Inmunosupresores/química , Inmunosupresores/farmacología , Antígenos/administración & dosificación , Antígenos/inmunología , Femenino , Ratones , Portadores de Fármacos/química , Alcohol Polivinílico/química , Células Presentadoras de Antígenos/inmunología , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/químicaRESUMEN
Growing evidence highlights the pivotal role of RORγt-innate lymphoid cells (ILCs) in the establishment of antitumor immune response and in enhancing tumor sensitivity to immunotherapy. Noteworthy, type 3 ILCs (ILC3s) have been recently acknowledged as an important class of antigen-presenting cells (APCs) in the context of host-microorganism interactions shaping the adaptive immune response in the intestinal mucosa. Although a broad range of mouse models has led to significant progress in untangling the role of ILC3s as APCs, the outcome of major histocompatibility complex (MHC)-dependent ILC-T cell crosstalk in colorectal cancer (CRC) remains underexplored in human. Moreover, expression of MHCII is confined to ILC3 subset, endowed with lymphoid tissue-inducing properties, that adopts tissue-specific fates and functions. Intestinal microbiota could dictate the plasticity of antigen-presenting ILC3s and we here summarize our current understanding of the functions of these cells in both mouse and human CRC discussing the role of microbiota as a key modulator of their tumor-suppressive activity.
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Células Presentadoras de Antígenos , Neoplasias Colorrectales , Microbioma Gastrointestinal , Linfocitos , Humanos , Animales , Microbioma Gastrointestinal/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/microbiología , Células Presentadoras de Antígenos/inmunología , Linfocitos/inmunología , Ratones , Inmunidad Innata , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiologíaRESUMEN
Foot and mouth disease (FMD) is a highly contagious infection caused by FMD-virus (FMDV) that affects livestock worldwide with significant economic impact. The main strategy for the control is vaccination with FMDV chemically inactivated with binary ethylenimine (FMDVi). In FMDV infection and vaccination, B cell response plays a major role by providing neutralizing/protective antibodies in animal models and natural hosts. Extracellular vesicles (EVs) and small EVs (sEVs) such as exosomes are important in cellular communication. EVs secreted by antigen-presenting cells (APC) like dendritic cells (DCs) participate in the activation of B and T cells through the presentation of native antigen membrane-associated to B cells or by transferring MHC-peptide complexes to T cells and even complete antigens from DCs. In this study, we demonstrate for the first time that APC activated with the FMDVi O1 Campos vaccine-antigens secrete EVs expressing viral proteins/peptides that could stimulate FMDV-specific immune response. The secretion of EVs-FMDVi is a time-dependent process and can only be isolated within the first 24 h post-activation. These vesicles express classical EVs markers (CD9, CD81, and CD63), along with immunoregulatory molecules (MHC-II and CD86). With an average size of 155 nm, they belong to the category of EVs. Studies conducted in vitro have demonstrated that EVs-FMDVi express antigens that can stimulate a specific B cell response against FMDV, including both marginal zone B cells (MZB) and follicular B cells (FoB). These vesicles can also indirectly or directly affect T cells, indicating that they express both B and T epitopes. Additionally, lymphocyte expansion induced by EVs-FMDVi is greater in splenocytes that have previously encountered viral antigens in vivo. The present study sheds light on the role of EVs derived from APC in regulating the adaptive immunity against FMDV. This novel insight contributes to our current understanding of the immune mechanisms triggered by APC during the antiviral immune response. Furthermore, these findings may have practical implications for the development of new vaccine platforms, providing a rational basis for the design of more effective vaccines against FMDV and other viral diseases.
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Células Presentadoras de Antígenos , Antígenos Virales , Linfocitos B , Vesículas Extracelulares , Virus de la Fiebre Aftosa , Fiebre Aftosa , Vacunas Virales , Animales , Virus de la Fiebre Aftosa/inmunología , Vesículas Extracelulares/inmunología , Linfocitos B/inmunología , Fiebre Aftosa/inmunología , Fiebre Aftosa/prevención & control , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos Virales/inmunología , Vacunas Virales/inmunología , Proteínas Virales/inmunología , Activación de Linfocitos/inmunología , Células Dendríticas/inmunología , Presentación de Antígeno/inmunologíaRESUMEN
Photothermal therapy is an alternative cancer therapy that uses a photothermal agent with light irradiation to induce fatal hyperthermia in cancer cells. In a previous study, we found that ex vivo photothermal (PT) treatment induced expression of heat shock proteins (HSPs), such as HSP70, HSP27, and HSP90, in cancer cells; moreover, immunization with lysates from PT-treated tumor cells resulted in significant tumor growth inhibition in tumor-bearing mice. In this study, we hypothesized that sublethal PT treatment of antigen-presenting cells regulates their immunogenicity. We observed the upregulation of expression of intracellular HSP70 and surface activation markers, such as CD40, CD80, CD86, and MHC class II, in sublethal PT-treated cells. The protumoral activity of myeloid-derived suppressor cells (MDSCs) was reduced by sublethal hyperthermia. Furthermore, poorly immunogenic MDSCs were converted into immunogenic antigen-presenting cells by PT treatment. The differences in immunogenicity between MDSCs untreated or treated with the PT technique were evaluated using the Student's t-test or Mann-Whitney rank sum test. Collectively, direct hyperthermic treatment resulted in phenotypic changes and the functional regulation of immune cells.
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Respuesta al Choque Térmico , Células Supresoras de Origen Mieloide , Terapia Fototérmica , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Animales , Ratones , Terapia Fototérmica/métodos , Línea Celular Tumoral , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Hipertermia Inducida/métodos , Ratones Endogámicos C57BL , Femenino , HumanosRESUMEN
Immunogenic cell death (ICD) holds the potential for in situ tumor vaccination while concurrently eradicating tumors and stimulating adaptive immunity. Most ICD inducers, however, elicit insufficient immune responses due to negative feedback against ICD biomarkers, limited infiltration of antitumoral immune cells, and the immunosuppressive tumor micro-environment (TME). Recent findings highlight the pivotal roles of stimulators of interferon gene (STING) activation, particularly in stimulating antigen-presenting cells (APCs) and TME reprogramming, addressing ICD limitations. Herein, we introduced 'tumor phagocytosis-driven STING activation', which involves the activation of STING in APCs during the recognition of ICD-induced cancer cells. We developed a polypeptide-based nanocarrier encapsulating both doxorubicin (DOX) and diABZI STING agonist 3 (dSA3) to facilitate this hypothesis in vitro and in vivo. After systemic administration, nanoparticles predominantly accumulated in tumor tissue and significantly enhanced anticancer efficacy by activating tumor phagocytosis-driven STING activation in MC38 and TC1 tumor models. Immunological activation of APCs occurred within 12 h, subsequently leading to the activation of T cells within 7 days, observed in both the TME and spleen. Furthermore, surface modification of nanoparticles with cyclic RGD (cRGD) moieties, which actively target integrin αvß3, enhances tumor accumulation and eradication, thereby verifying the establishment of systemic immune memory. Collectively, this study proposes the concept of tumor phagocytosis-driven STING activation and its effectiveness in generating short-term and long-term immune responses.
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Doxorrubicina , Proteínas de la Membrana , Ratones Endogámicos C57BL , Fagocitosis , Microambiente Tumoral , Animales , Proteínas de la Membrana/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Fagocitosis/efectos de los fármacos , Doxorrubicina/administración & dosificación , Femenino , Nanopartículas/administración & dosificación , Nanopartículas/química , Línea Celular Tumoral , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Ratones , Muerte Celular Inmunogénica/efectos de los fármacos , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/efectos de los fármacos , Antibióticos Antineoplásicos/administración & dosificación , Humanos , Péptidos/administración & dosificación , Péptidos/químicaRESUMEN
In this issue of Cancer Cell, Espinosa-Carrasco et al. show that the efficacy of cancer immunotherapies depends upon the formation of intratumoral immune triads between antigen-presenting cells and antigen-specific CD4+ and CD8+ T cells. This interaction reprograms tumor-specific CD8+ T cells to exert potent effector functions and eradicate established solid tumors.
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Linfocitos T CD8-positivos , Neoplasias , Linfocitos T CD8-positivos/inmunología , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Inmunoterapia/métodos , Animales , Linfocitos T CD4-Positivos/inmunología , Células Presentadoras de Antígenos/inmunología , RatonesRESUMEN
An obstacle in current tumor immunotherapies lies in the challenge of achieving sustained and tumor-targeting T cell immunity, impeded by the limited antigen processing and cross-presentation of tumor antigens. Here, we propose a hydrogel-based multicellular immune factory within the body that autonomously converts tumor cells into an antitumor vaccine. Within the body, the scaffold, formed by a calcium-containing chitosan hydrogel complex (ChitoCa) entraps tumor cells and attracts immune cells to establish a durable and multicellular microenvironment. Within this context, tumor cells are completely eliminated by antigen-presenting cells (APCs) and processed for cross-antigen presentation. The regulatory mechanism relies on the Mincle receptor, a cell-phagocytosis-inducing C-type lectin receptor specifically activated on ChitoCa-recruited APCs, which serves as a recognition synapse, facilitating a tenfold increase in tumor cell engulfment and subsequent elimination. The ChitoCa-induced tumor cell processing further promotes the cross-presentation of tumor antigens to prime protective CD8+ T cell responses. Therefore, the ChitoCa treatment establishes an immune niche within the tumor microenvironment, resulting in effective tumor regression either used alone or in combination with other immunotherapies. This hydrogel-induced immune factory establishes a functional organ-like multicellular colony for tumor-specific immunotherapy, paving the way for innovative strategies in cancer treatment.
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Hidrogeles , Inmunoterapia , Lectinas Tipo C , Inmunoterapia/métodos , Animales , Hidrogeles/química , Lectinas Tipo C/metabolismo , Humanos , Línea Celular Tumoral , Neoplasias/terapia , Neoplasias/inmunología , Ratones Endogámicos C57BL , Microambiente Tumoral/inmunología , Quitosano/química , Células Presentadoras de Antígenos/inmunología , Vacunas contra el Cáncer/inmunología , Ratones , Proteínas de la Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Linfocitos T CD8-positivos/inmunologíaRESUMEN
Skin-resident antigen-presenting cells (APC) play an important role in maintaining peripheral tolerance via immune checkpoint proteins and induction of T regulatory cells (Tregs). However, there is a lack of knowledge on how to expand or recruit immunoregulatory cutaneous cells without causing inflammation. Here, it is shown that administration of a non-coding single-stranded oligonucleotide (ssON) leads to CCR2-dependent accumulation of CD45+CD11b+Ly6C+ cells in the skin that express substantial levels of PD-L1 and ILT3. Transcriptomic analyses of skin biopsies reveal the upregulation of key immunosuppressive genes after ssON administration. Functionally, the cutaneous CD11b+ cells inhibit Th1/2/9 responses and promote the induction of CD4+FoxP3+ T-cells. In addition, ssON treatment of imiquimod-induced inflammation results in significantly reduced Th17 responses. It is also shown that induction of IL-10 production in the presence of cutaneous CD11b+ cells isolated after ssON administrations is partly PD-L1 dependent. Altogether, an immunomodulatory ssON is identified that can be used therapeutically to recruit cutaneous CD11b+ cells with the capacity to dampen Th cells.
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Antígeno CD11b , Piel , Linfocitos T Reguladores , Linfocitos T Reguladores/inmunología , Ratones , Animales , Antígeno CD11b/metabolismo , Antígeno CD11b/genética , Antígeno CD11b/inmunología , Piel/inmunología , Piel/metabolismo , Ratones Endogámicos C57BL , Oligonucleótidos/farmacología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Femenino , Modelos Animales de EnfermedadRESUMEN
Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.
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Células Presentadoras de Antígenos , Vacunas contra el Cáncer , Inmunoterapia , Nanopartículas , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Nanopartículas/administración & dosificación , Células Presentadoras de Antígenos/inmunología , Biomimética/métodos , Materiales Biomiméticos/administración & dosificación , Animales , Liposomas , NanovacunasRESUMEN
Antigen-presenting cells (APCs) play an important role in virus infection control by bridging innate and adaptive immune responses. Macrophages and dendritic cells (DCs) possess various surface receptors to recognize/internalize antigens, and antibody binding can enhance pathogen-opsonizing uptake by these APCs via interaction of antibody fragment crystallizable (Fc) domains with Fc receptors, evoking profound pathogen control in certain settings. Here, we examined phagocytosis-enhancing potential of Fc domains directly oriented on a retroviral virion/virus-like particle (VLP) surface. We generated an expression vector coding a murine Fc fragment fused to the transmembrane region (TM) of a retroviral envelope protein, deriving expression of the Fc-TM fusion protein on the transfected cell surface and production of virions incorporating the chimeric Fc upon co-transfection. Incubation of Fc-displaying simian immunodeficiency virus (SIV) with murine J774 macrophages and bone marrow-derived DCs derived Fc receptor-dependent enhanced uptake, being visualized by imaging cytometry. Alternative preparation of a murine leukemia virus (MLV) backbone-based Fc-displaying VLP loading an influenza virus hemagglutinin (HA) antigen resulted in enhanced HA internalization by macrophages, stating antigen compatibility of the design. Results show that the Fc-TM fusion molecule can be displayed on certain viruses/VLPs and may be utilized as a molecular adjuvant to facilitate APC antigen uptake.
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Células Presentadoras de Antígenos , Células Dendríticas , Fragmentos Fc de Inmunoglobulinas , Virión , Animales , Ratones , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/metabolismo , Fragmentos Fc de Inmunoglobulinas/inmunología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Virión/metabolismo , Virión/genética , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Línea Celular , Virus de la Leucemia Murina/genética , Fagocitosis , HumanosRESUMEN
Despite the tremendous clinical potential of nucleic acid-based vaccines, their efficacy to induce therapeutic immune response has been limited by the lack of efficient local gene delivery techniques in the human body. In this study, we develop a hydrogel-based organic electronic device (µEPO) for both transdermal delivery of nucleic acids and in vivo microarrayed cell electroporation, which is specifically oriented toward one-step transfection of DNAs in subcutaneous antigen-presenting cells (APCs) for cancer immunotherapy. The µEPO device contains an array of microneedle-shaped electrodes with pre-encapsulated dry DNAs. Upon a pressurized contact with skin tissue, the electrodes are rehydrated, electrically triggered to release DNAs, and then electroporate nearby cells, which can achieve in vivo transfection of more than 50% of the cells in the epidermal and upper dermal layer. As a proof-of-concept, the µEPO technique is employed to facilitate transdermal delivery of neoantigen genes to activate antigen-specific immune response for enhanced cancer immunotherapy based on a DNA vaccination strategy. In an ovalbumin (OVA) cancer vaccine model, we show that high-efficiency transdermal transfection of APCs with OVA-DNAs induces robust cellular and humoral immune responses, including antigen presentation and generation of IFN-γ+ cytotoxic T lymphocytes with a more than 10-fold dose sparing over existing intramuscular injection (IM) approach, and effectively inhibits tumor growth in rodent animals.