RESUMO
T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8+ tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8+ tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.
Assuntos
Imunoterapia Adotiva/métodos , Interleucina-10/farmacologia , Neoplasias/terapia , Fosforilação Oxidativa/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Animais , Proteínas de Transporte de Ânions/genética , Proteínas de Transporte de Ânions/metabolismo , Linhagem Celular Tumoral , Terapia Combinada/métodos , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Células HEK293 , Meia-Vida , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Fragmentos Fc das Imunoglobulinas/farmacologia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Interleucina-10/uso terapêutico , Camundongos , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Interleucina-10/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismoRESUMO
Myelofibrosis usually occurs either as a part of a myelodysplastic syndrome or in conjunction with neoplasia. It is not commonly thought of an autoimmune disease. We reported that p40-/-IL-2Rα-/- (interleukin-12p40 and interleukin-2 receptor alpha double knockout) mice, a mouse model of human primary biliary cholangitis, exhibited features consistent with autoimmune myelofibrosis, including anemia associated with bone marrow fibrosis, and extramedullary hematopoiesis (EMH) including LSK (Lineage-c-Kit+Sca-1+) cells in spleen, liver and peripheral blood. There were also increased LSK cells in bone marrow but they demonstrated impaired hematopoiesis. Importantly effector memory T cells that infiltrated the bone marrow of p40-/-IL-2Rα-/- mice manifested a higher ability to produce IFN-γ. CD8+ T cells, already known to play a dominate role in portal inflammation, were also key for bone marrow dysregulation and EMH. IFN-γ was the key cytokine that induced bone marrow fibrosis, bone marrow failure and EMH. Finally anti-CD8α antibody therapy fully protected p40-/-IL-2Rα-/- mice from autoimmune myelofibrosis. In conclusion, our results demonstrate that CD8+ T cells and IFN-γ are associated with autoimmune myelofibrosis, a finding that may allow targeting of CD8+ T cells and IFN-γ as a therapeutic targets.
Assuntos
Doenças Autoimunes/imunologia , Medula Óssea/patologia , Linfócitos T CD8-Positivos/imunologia , Colangite/imunologia , Cirrose Hepática Biliar/imunologia , Fígado/fisiologia , Mielofibrose Primária/imunologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Modelos Animais de Doenças , Fibrose , Hematopoese Extramedular , Humanos , Memória Imunológica , Interferon gama/metabolismo , Subunidade p40 da Interleucina-12/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-2/genéticaRESUMO
Two Gram-staining-positive, aerobic, motile, endospore-forming, rod-shaped bacteria, designated strains Y24(T) and H9(T) were isolated from cold spring and carrot (Daucus L.) samples, respectively, in Xinjiang Uyghur Autonomous Region, north-western China. The taxonomic positions of the two new isolates were determined by using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences and DNA-DNA hybridizations showed that strains Y24(T) and H9(T) were two different novel species belonging to the genus Paenibacillus, with Paenibacillus hunanensis FeL05(T) as their closest relative. The genomic DNA G + C contents of the two isolates Y24(T) and H9(T) were 48.1 and 46.6 mol %, respectively. The cell wall peptidoglycan contained meso-diaminopimelic acid. The predominant menaquinone was both as MK-7. The major cellular fatty acids were anteiso-C15:0, C16:0, iso-C16:0, anteiso-C17:0 and iso-C15:0. The polar lipid profiles consisted of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and two glycolipids as the major components. On the basis of their phenotypic characteristics, the two isolates represent two different novel species of the genus Paenibacillus, for which the names Paenibacillus wulumuqiensis sp. nov. (type strain Y24(T) = CPCC 100602(T) = JCM 30284(T)) and Paenibacillus dauci sp. nov. (type strain H9(T) = CPCC 100608(T) = JCM 30283(T)) are proposed.
Assuntos
Paenibacillus/classificação , Filogenia , Composição de Bases , Parede Celular/química , China , Ácido Diaminopimélico/análise , Ácidos Graxos/análise , Genoma Bacteriano/genética , Glicolipídeos/análise , Hibridização de Ácido Nucleico , Paenibacillus/genética , Peptidoglicano/química , RNA Ribossômico 16S/genética , Especificidade da EspécieRESUMO
A rose, Gram-stain-negative, aerobic, rod-shaped bacterium that was motile by gliding, and designated strain H359(T), was isolated from radiation-polluted soil (with high Cs(137)) from the Xinjiang Uygur Autonomous Region of PR China and subjected to a polyphasic taxonomic analysis. The isolate grew optimally at 30 °C and pH 7.0. It grew with NaCl up to 4% (w/v). 16S rRNA gene sequence analysis indicated that strain H359(T) belonged to the genus Rufibacter, a member of the family Cytophagaceae, with Rufibacter tibetensis CCTCC AB 208084(T) as its closest phylogenetic relative, having 96.1% 16S rRNA gene sequence similarity to the type strain. Strain H359(T) contained menaquinone-7 (MK-7) as the predominant menaquinone, and the major fatty acids were iso-C15 : 0, summed feature 4 (iso-C17 : 1 I and/or anteiso-C17 : 1 B), summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c) and C16 : 1ω5c. The polar lipid profile had phosphatidylethanolamine as the major component. The DNA G+C content was 43.9 mol%. Based on phenotypic, genotypic and phylogenetic evidence, strain H359(T) represents a novel species of the genus Rufibacter, for which the name Rufibacter roseus sp. nov. is proposed. The type strain is H359(T) (â=CPCC 100615(T)â=KCTC 42217(T)).
Assuntos
Cytophagaceae/classificação , Filogenia , Microbiologia do Solo , Técnicas de Tipagem Bacteriana , Composição de Bases , China , Cytophagaceae/genética , Cytophagaceae/isolamento & purificação , DNA Bacteriano/genética , Ácidos Graxos/química , Dados de Sequência Molecular , Fosfatidiletanolaminas/química , Pigmentação , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Poluentes Radioativos do Solo , Vitamina K 2/análogos & derivados , Vitamina K 2/químicaRESUMO
Despite the array of mammalian transgene switches available for regulating therapeutic protein expression in response to small molecules or physical stimuli, issues remain, including cytotoxicity of chemical inducers and limited biocompatibility of physical cues. This study introduces gene switches driven by short peptides comprising eight or fewer amino acid residues. Utilizing a competence regulator (ComR) and sigma factor X-inducing peptide (XIP) from Streptococcus vestibularis as the receptor and inducer, respectively, this study develops two strategies for a peptide-activated transgene control system. The first strategy involves fusing ComR with a transactivation domain and utilizes ComR-dependent synthetic promoters to drive expression of the gene-of-interest, activated by XIP, thereby confirming its membrane penetrability and intracellular functionality. The second strategy features an orthogonal synthetic receptor exposing ComR extracellularly (ComREXTRA), greatly increasing sensitivity with exceptional responsiveness to short peptides. In a proof-of-concept study, peptides are administered to type-1 diabetic mice with microencapsulated engineered human cells expressing ComREXTRA for control of insulin expression, restoring normoglycemia. It is envisioned that this system will encourage the development of short peptide drugs and promote the introduction of non-toxic, orthogonal, and highly biocompatible personalized biopharmaceuticals for gene- and cell-based therapies.
Assuntos
Peptídeos , Animais , Camundongos , Humanos , Peptídeos/genética , Peptídeos/farmacologia , Peptídeos/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/terapia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , TransgenesRESUMO
To further explore the characteristics of heavy metal pollution and the ecological risk of typical industries in reclaimed soil, based on data from 315 different depth profiles of soil samples collected from 49 plots in Jiading District, Shanghai, the geo-accumulation index and potential ecological risk index were used to evaluate the contents and potential ecological risk of seven heavy metals, namely Cd, Pb, Cu, Zn, Ni, Hg, and As. The APCS-MLR receptor model and PMF positive matrix factorization model were employed to analyze the pollution sources. The results showed that:â except for As, the contents of other heavy metals in the soil of the study area exceeded the Shanghai soil background values to varying degrees. The contents of Cd, Pb, Cu, Zn, Ni, and Hg in the surface soil were 3.54, 2.34, 2.91, 1.20, 3.75, and 4.40 times the background values, respectively. The contents of heavy metals in the soil decreased with the increase in depth, and heavy metals were enriched to a certain extent in the surface soil, indicating that human activities had an impact on the distribution of heavy metals in the soil. â¡ The APCS-MLR and PMF receptor models identified four main sources of soil heavy metals in the study area. Source 1 (Cu, Zn, and Pb) was a mixture of metal products and automobile manufacturing, source 2 (Ni and Cd) was electroplating enterprises, source 3 (Hg) was mainly from chemical enterprises, and source 4 (As) was natural. The combined use of the two receptor models further improved the accuracy and credibility of source identification. ⢠The geo-accumulation index in descending order was Hg(1.54)>Ni(1.32)>Cd(1.21)>Cu(0.96)>Pb(0.64)>Zn(-0.33)>As(-1.02). The potential ecological risk index showed that the comprehensive potential ecological risk index RI value in the study area ranged from 32.50 to 4 910.97, with a mean of 321.40, indicating a strong potential ecological risk. The pollution values of heavy metals Hg, Ni, and Cd in industrial site soil deserve further attention for re-development and utilization purposes.
RESUMO
Five new sesquiterpenoids, (4S, 5S, 6S, 7S, 8 R)-5,6-dihydroxy-1-acetoxy-10(14)-en-britannilactone (1), (4S, 5 R, 6S, 7S, 8 R)-5,6-dihydroxy-1-acetoxy-10(14)-en-britannilactone (2), 6-O-propionyl-britannilactone (3), 1ß-hydroxy-3α-acetoxyeudesma-11(13)-en-12,8ß-olide (4) and 1ß,5ß-dihydroxyeudesma-11(13)-en-12,8ß-olide (5), along with twelve known ones were isolated from the flowers of Pentanema britannicum (L.) D.Gut.Larr. Among them, compounds 1 and 2 were stereoisomers which belong to 1,10-seco-eudesmane sesquiterpenoid with rare double bond between C-10 and C-14. The structures of the isolated compounds were elucidated by various spectroscopic methods, including 1D and 2D NMR experiments.
RESUMO
The success of chimeric antigen receptor (CAR) T cell therapy in treating several hematopoietic malignancies has been difficult to replicate in solid tumors, in part because of T cell exhaustion and eventually dysfunction. To counter T cell dysfunction in the tumor microenvironment, we metabolically armored CAR T cells by engineering them to secrete interleukin-10 (IL-10). We show that IL-10 CAR T cells preserve intact mitochondrial structure and function in the tumor microenvironment and increase oxidative phosphorylation in a mitochondrial pyruvate carrier-dependent manner. IL-10 secretion promoted proliferation and effector function of CAR T cells, leading to complete regression of established solid tumors and metastatic cancers across several cancer types in syngeneic and xenograft mouse models, including colon cancer, breast cancer, melanoma and pancreatic cancer. IL-10 CAR T cells also induced stem cell-like memory responses in lymphoid organs that imparted durable protection against tumor rechallenge. Our results establish a generalizable approach to counter CAR T cell dysfunction through metabolic armoring, leading to solid tumor eradication and long-lasting immune protection.
RESUMO
Colletotrichum species are plant pathogens, saprobes and endophytes on various plant hosts. It is regarded as one of the 10 most important genera of plant pathogens in the world. Walnut anthracnose is one of the most severe diseases affecting walnut productivity and quality in China. In this study, 162 isolates were obtained from 30 fruits and 65 leaf samples of walnut collected in Beijing, China. Based on morphological characteristics and DNA sequence analyses of the concatenated loci, namely internal transcribed spacer (ITS), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), actin (ACT), chitin synthase 1 (CHS-1) and beta-tubulin (TUB2), these isolates were identified as two novel species of Colletotrichum, i.e. C.juglandicola and C.peakense. Koch's postulates indicated that both C.juglandicola and C.peakense could cause anthracnose in walnut.
RESUMO
HIV infection has been reported to cause bone loss and a higher risk of fracture. Under normal conditions, bone metabolism is regulated by mesenchymal cells, osteoclasts differentiated from mononuclear macrophages, osteoblasts, and their expression of regulatory factors, such as receptor activator of nuclear factor-kappa B ligand (RANKL), M-SCF, and transforming growth factor-beta. The balance between bone resorption and osteogenesis depends on the balance between osteoclasts and osteoblasts. In addition, some immune cells, such as B-cells, T-cells, and other non-immune cells expressing RANKL, can contribute to osteoporosis under inflammatory conditions. HIV proteins consist of three types: regulatory proteins, accessory proteins, and structural proteins, which contribute to HIV-mediated bone loss partly by upregulating NF-κB expression, tumor necrosis factor alpha content, and release of inflammatory cytokines. Even worse, although antiretroviral therapy has reduced HIV infection mortality and successfully transformed acquired immunodeficiency syndrome into a chronic disease, its impact on bone loss should not be overlooked, especially when the drug contains tenofovir. This review analyzes some reports focusing on the overall osteolytic situation due to imbalances in osteogenesis and bone resorption due to HIV infection and antiviral therapy. The intrinsic mechanism of bone loss provides a reference for researchers to analyze the risk factors for HIV patients complicated with bone loss and helps clinicians to provide ideas for the intervention and prevention of bone loss during clinical treatment and chronic disease management of HIV patients.
Assuntos
Reabsorção Óssea , Infecções por HIV , Humanos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Osteoclastos/metabolismo , Osteoclastos/patologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Reabsorção Óssea/prevenção & controle , Osteogênese , Osteoblastos/metabolismo , Osteoblastos/patologia , Ligante RANK/metabolismoRESUMO
Many human cancers manifest the capability to circumvent attack by the adaptive immune system. In this work, we identified a component of immune evasion that involves frequent up-regulation of fragile X mental retardation protein (FMRP) in solid tumors. FMRP represses immune attack, as revealed by cancer cells engineered to lack its expression. FMRP-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, FMRP's immunosuppression was multifactorial, involving repression of the chemoattractant C-C motif chemokine ligand 7 (CCL7) concomitant with up-regulation of three immunomodulators-interleukin-33 (IL-33), tumor-secreted protein S (PROS1), and extracellular vesicles. Gene signatures associate FMRP's cancer network with poor prognosis and response to therapy in cancer patients. Collectively, FMRP is implicated as a regulator that orchestrates a multifaceted barrier to antitumor immune responses.
Assuntos
Proteína do X Frágil da Deficiência Intelectual , Evasão da Resposta Imune , Tolerância Imunológica , Neoplasias , Animais , Humanos , Camundongos , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Neoplasias/imunologia , Quimiocina CCL7/metabolismo , Interleucina-33 , Proteína S/metabolismoRESUMO
A Gram-stain-positive, endospore-forming, rod-shaped bacterium, designated XJ259(T), was isolated from a cold spring sample from Xinjiang Uyghur Autonomous Region, China. The isolate grew optimally at 20-30 °C and pH 7.3-7.8. Comparative analysis of the 16S rRNA gene sequence showed that isolate XJ259(T) belonged phylogenetically to the genus Paenibacillus, and was most closely related to Paenibacillus xinjiangensis B538(T) (with 96.6â% sequence similarity), Paenibacillus glycanilyticus DS-1(T) (96.3â%) and Paenibacillus castaneae Ch-32(T) (96.1â%), sharing less than 96.0â% sequence similarity with all other members of the genus Paenibacillus. Chemotaxonomic analysis revealing menaquinone-7 (MK-7) as the major isoprenoid quinone, diphosphatidylglycerol, phosphatidylethanolamine and two unknown phosphoglycolipids as the major cellular polar lipids, a DNA G+C content of 47.0 mol%, and anteiso-C15:0 and C16:0 as the major fatty acids supported affiliation of the new isolate to the genus Paenibacillus. Based on these data, isolate XJ259(T) is considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus algorifonticola sp. nov. is proposed. The type strain is XJ259(T) (â=âCGMCC 1.10223(T) â=âJCM 16598(T)).
Assuntos
Água Doce/microbiologia , Paenibacillus/classificação , Paenibacillus/isolamento & purificação , Técnicas de Tipagem Bacteriana , Composição de Bases , China , Análise por Conglomerados , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Ácidos Graxos/análise , Concentração de Íons de Hidrogênio , Dados de Sequência Molecular , Paenibacillus/genética , Paenibacillus/fisiologia , Fosfolipídeos/análise , Filogenia , Quinonas/análise , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Esporos Bacterianos/citologia , TemperaturaRESUMO
Immune stimulatory antibodies and cytokines elicit potent antitumor immunity. However, the dose-limiting systemic toxicity greatly hinders their clinical applications. Here, we demonstrate a chemical approach, termed "switchable" immune modulator (Sw-IM), to limit the systemic exposure and therefore ameliorate their toxicities. Sw-IM is a biomacromolecular therapeutic reversibly masked by biocompatible polymers through chemical linkers that are responsive to tumor-specific stimuli, such as high reducing potential and acidic pH. Sw-IMs stay inert (switch off) in the circulation and healthy tissues but get reactivated (switch on) selectively in tumor via responsive removal of the polymer masks, thus focusing the immune boosting activities in the tumor microenvironment. Sw-IMs applied to anti4-1BB agonistic antibody and IL-15 cytokine led to equivalent antitumor efficacy to the parental IMs with markedly reduced toxicities. Sw-IM provides a highly modular and generic approach to improve the therapeutic window and clinical applicability of potent IMs in mono- and combinational immunotherapies.
RESUMO
Malignant transformation and tumour progression are associated with cancer-cell softening. Yet how the biomechanics of cancer cells affects T-cell-mediated cytotoxicity and thus the outcomes of adoptive T-cell immunotherapies is unknown. Here we show that T-cell-mediated cancer-cell killing is hampered for cortically soft cancer cells, which have plasma membranes enriched in cholesterol, and that cancer-cell stiffening via cholesterol depletion augments T-cell cytotoxicity and enhances the efficacy of adoptive T-cell therapy against solid tumours in mice. We also show that the enhanced cytotoxicity against stiffened cancer cells is mediated by augmented T-cell forces arising from an increased accumulation of filamentous actin at the immunological synapse, and that cancer-cell stiffening has negligible influence on: T-cell-receptor signalling, production of cytolytic proteins such as granzyme B, secretion of interferon gamma and tumour necrosis factor alpha, and Fas-receptor-Fas-ligand interactions. Our findings reveal a mechanical immune checkpoint that could be targeted therapeutically to improve the effectiveness of cancer immunotherapies.
Assuntos
Imunoterapia Adotiva , Neoplasias , Animais , Imunoterapia , Interferon gama , Camundongos , Neoplasias/terapia , Linfócitos TRESUMO
Interleukin-2 (IL-2) is a potent T-cell mitogen that can adjuvant anti-cancer adoptive T-cell transfer (ACT) immunotherapy by promoting T-cell engraftment. However, the clinical applications of IL-2 in combination with ACT are greatly hindered by the severe adverse effects such as vascular leak syndrome (VLS). Here, we developed a synthetic delivery strategy for IL-2 via backpacking redox-responsive IL-2/Fc nanogels (NGs) to the plasma membrane of adoptively transferred T-cells. The NGs prepared by traceless chemical cross-linking of cytokine proteins selectively released the cargos in response to T-cell receptor activation upon antigen recognition in tumors. We found that IL-2/Fc delivered by T-cell surface-bound NGs expanded transferred tumor-reactive T-cells 80-fold more than the free IL-2/Fc of an equivalent dose administered systemically and showed no effects on tumor-infiltrating regulatory T-cell expansion. Intriguingly, IL-2/Fc NG backpacks that facilitated a sustained and slow release of IL-2/Fc also promoted the CD8+ memory precursor differentiation and induced less T-cell exhaustion in vitro compared to free IL-2/Fc. The controlled responsive delivery of IL-2/Fc enabled the safe administration of repeated doses of the stimulant cytokine with no overt toxicity and improved efficacy against melanoma metastases in a mice model.
Assuntos
Interleucina-2/farmacologia , Melanoma/patologia , Polietilenoglicóis/farmacologia , Polietilenoimina/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Interleucina-2/síntese química , Interleucina-2/química , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Nanogéis , Oxirredução , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoimina/síntese química , Polietilenoimina/química , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Cancer immunotherapy has recently shown dramatic clinical success inducing durable response in patients of a wide variety of malignancies. Further improvement of the clinical outcome with immune related cancer treatment requests more exquisite manipulation of a patient's immune system with increased immunity against diseases while mitigating the toxicities. To meet this challenge, biomaterials applied to immunoengineering are being developed to achieve tissue- and/or cell-specific immunomodulation and thus could potentially enhance both the efficacy and safety of current cancer immunotherapies. Here, we review the recent advancement in the field of immunoengineering using biomaterials and their applications in promoting different modalities of cancer immunotherapies, with focus on cell-, antibody-, immunomodulator-, and gene-based immune related treatments and their combinations with conventional therapies. Challenges and opportunities are discussed in applying biomaterials engineering strategies in the development of future cancer immunotherapies. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanomaterials and Implants.
Assuntos
Materiais Biocompatíveis , Imunoterapia , Neoplasias/terapia , Engenharia de Proteínas , Transferência Adotiva , Animais , Anticorpos , Humanos , CamundongosRESUMO
Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to 'backpack' large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface-conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.
Assuntos
Sistemas de Liberação de Medicamentos , Imunoterapia Adotiva , Nanopartículas , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Animais , Proliferação de Células , Citocinas/administração & dosagem , Humanos , Interleucina-15/administração & dosagem , Antígenos Comuns de Leucócito/imunologia , Ativação Linfocitária , Camundongos , Linfócitos T/citologia , Linfócitos T/metabolismo , Microambiente TumoralRESUMO
Autoimmune diseases often induce dysregulated hematopoiesis with altered number and function of hematopoietic stem and progenitor cells (HSPCs). However, there are limited studies on the direct regulation of HSPCs on T cells, which are often detrimental to autoimmunity. Here, we found that in a murine model of Concanavalin A-induced autoimmune hepatitis, LSK (Lineage-Sca-1+c-Kit+)-like cells accumulated in liver, spleen, and bone marrow (BM), which were myeloid progenitors (Lineage-Sca-1-c-Kit+) that upregulated Sca-1 expression upon T cell-derived IFN-γ stimulation. Strikingly, BM LSK-like cells from mice induced by Con A to develop autoimmune hepatitis or alternatively myeloid progenitors from wild-type mice possessed strong in vitro suppressive ability. Their suppressive function depended on T cell-derived IFN-γ in a paracrine fashion, which induced STAT1 phosphorylation, inducible nitric oxide synthase expression, and nitric oxide production. Blocking IFN-γ/IFN-γ receptor interaction, knockout of STAT1, or iNOS inhibition abrogated their suppressive function. In addition, the suppressive function was independent of differentiation; mitomycin C-treated myeloid progenitors maintained T cell suppressive ability in vitro. Our data demonstrate a mechanism of inflammation induced suppressive function of myeloid progenitors, which may participate directly in suppressing T cell-mediated immunopathology.
RESUMO
Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that develops based upon the interaction of genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified dozens of predisposing variants including HLA, IL12A, and CTLA4 but have been disappointed in identifying a "smoking gun." These discoveries highlight the importance of the genetic background involved in immunological dysregulation. Although concordance rate of PBC in monozygotic (MZ) twins is among the highest reported in autoimmune disorders, incomplete disease concordance in twins associated with differentially expressed genes has been demonstrated. However, little is understood about how environmental aspects contribute to the disease and why middle-aged women are more susceptible. As a result, epigenetic factors, which convert signals indicating environmental changes into dynamic and heritable alterations of transcriptional potential, are getting increased attention by researchers in both basic and clinical studies. Among epigenetic mechanisms, the instability and skewed gene expression in the X chromosome may account for the female preponderance in PBC. In addition, transcriptional regulation of histone modification and DNA methylation underscores potential involvement in disease pathogenesis. High-throughput techniques are being used to identify epigenetic regulators. In this review, we attempt to outline recent progress regarding epigenetics in PBC and other autoimmune diseases.
Assuntos
Epigênese Genética , Predisposição Genética para Doença , Cirrose Hepática Biliar/genética , Animais , Autoimunidade/genética , Metilação de DNA , Regulação da Expressão Gênica , Histonas/metabolismo , Humanos , Cirrose Hepática Biliar/imunologia , Cirrose Hepática Biliar/metabolismo , MicroRNAs/genética , RNA Longo não Codificante/genética , Inativação do Cromossomo XRESUMO
Understanding the mechanisms that lead to autoimmunity is critical for defining potential therapeutic pathways. In this regard there have been considerable efforts in investigating the interacting roles of TGF-ß and IL-2 on the function regulatory T cells. We have taken advantage of dnTGF-ßRII Il2ra-/- (abbreviated as Il2ra-/-Tg) mouse model, which allows a direct mechanistic approach to define the relative roles of TGF-ß and IL-2 on Treg development. Il2ra-/-Tg mice spontaneously developed multi-organ autoimmune diseases with expansion of pathogenic T cells and enhanced germinal center response at 3-4 weeks of age. Importantly, peripheral Treg cells from Il2ra-/-Tg mice demonstrated an activated Th1-like stable phenotype and normal in vitro suppressive function, while thymus Treg increased but manifested decreased suppressive function. Interestingly, neither thymus nor peripheral Treg cells of Il2ra-/-Tg mice contained Neuropilin-1+ or PD-1hi phenotype, resulting in defective follicular regulatory T (Tfr) cell development. Such defective Tfr development led to elevated follicular T helper cells, enhanced germinal center responses and increased plasma cell infiltration. These data demonstrate an important synergetic role of TGF-ß and IL-2 in the generation, activation and stability of Treg cells, as well as their subsequent development into Tfr cells.