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1.
Adv Drug Deliv Rev ; 210: 115332, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38759702

RESUMO

Recent advancements in genomics, transcriptomics, and metabolomics have significantly advanced our understanding of the human gut microbiome and its impact on the efficacy and toxicity of anti-cancer therapeutics, including chemotherapy, immunotherapy, and radiotherapy. In particular, prebiotics, probiotics, and postbiotics are recognized for their unique properties in modulating the gut microbiota, maintaining the intestinal barrier, and regulating immune cells, thus emerging as new cancer treatment modalities. However, clinical translation of microbiome-based therapy is still in its early stages, facing challenges to overcome physicochemical and biological barriers of the gastrointestinal tract, enhance target-specific delivery, and improve drug bioavailability. This review aims to highlight the impact of prebiotics, probiotics, and postbiotics on the gut microbiome and their efficacy as cancer treatment modalities. Additionally, we summarize recent innovative engineering strategies designed to overcome challenges associated with oral administration of anti-cancer treatments. Moreover, we will explore the potential benefits of engineered gut microbiome-modulating approaches in ameliorating the side effects of immunotherapy and chemotherapy.

2.
ACS Nano ; 18(15): 10439-10453, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38567994

RESUMO

The cGAS-STING pathway plays a crucial role in innate immune activation against cancer and infections, and STING agonists based on cyclic dinucleotides (CDN) have garnered attention for their potential use in cancer immunotherapy and vaccines. However, the limited drug-like properties of CDN necessitate an efficient delivery system to the immune system. To address these challenges, we developed an immunostimulatory delivery system for STING agonists. Here, we have examined aqueous coordination interactions between CDN and metal ions and report that CDN mixed with Zn2+ and Mn2+ formed distinctive crystal structures. Further pharmaceutical engineering led to the development of a functional coordination nanoparticle, termed the Zinc-Mn-CDN Particle (ZMCP), produced by a simple aqueous one-pot synthesis. Local or systemic administration of ZMCP exerted robust antitumor efficacy in mice. Importantly, recombinant protein antigens from SARS-CoV-2 can be simply loaded during the aqueous one-pot synthesis. The resulting ZMCP antigens elicited strong cellular and humoral immune responses that neutralized SARS-CoV-2, highlighting ZMCP as a self-adjuvant vaccine platform against COVID-19 and other infectious pathogens. Overall, this work establishes a paradigm for developing translational coordination nanomedicine based on drug-metal ion coordination and broadens the applicability of coordination medicine for the delivery of proteins and other biologics.


Assuntos
Nanopartículas , Neoplasias , Vacinas , Animais , Camundongos , Neoplasias/terapia , Adjuvantes Imunológicos , Imunoterapia/métodos , Nanopartículas/química
3.
Front Immunol ; 15: 1329846, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38529279

RESUMO

Understanding adaptive immunity against SARS-CoV-2 is a major requisite for the development of effective vaccines and treatments for COVID-19. CD4+ T cells play an integral role in this process primarily by generating antiviral cytokines and providing help to antibody-producing B cells. To empower detailed studies of SARS-CoV-2-specific CD4+ T cell responses in mouse models, we comprehensively mapped I-Ab-restricted epitopes for the spike and nucleocapsid proteins of the BA.1 variant of concern via IFNγ ELISpot assay. This was followed by the generation of corresponding peptide:MHCII tetramer reagents to directly stain epitope-specific T cells. Using this rigorous validation strategy, we identified 6 immunogenic epitopes in spike and 3 in nucleocapsid, all of which are conserved in the ancestral Wuhan strain. We also validated a previously identified epitope from Wuhan that is absent in BA.1. These epitopes and tetramers will be invaluable tools for SARS-CoV-2 antigen-specific CD4+ T cell studies in mice.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Camundongos , Linfócitos T CD4-Positivos , Epitopos de Linfócito T , Nucleocapsídeo/química , Peptídeos/química , SARS-CoV-2/química , Antígenos de Histocompatibilidade Classe II/química , Glicoproteína da Espícula de Coronavírus/química
4.
J Control Release ; 368: 768-779, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38492861

RESUMO

Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults with a 5-year survival rate of 30.5%. These poor patient outcomes are attributed to tumor relapse, stemming from ineffective innate immune activation, T cell tolerance, and a lack of immunological memory. Thus, new strategies are needed to activate innate and effector immune cells and evoke long-term immunity against AML. One approach to address these issues is through Stimulator of Interferon Genes (STING) pathway activation, which produces Type I Interferons (Type I IFN) critical for innate and adaptive immune activation. Here, we report that systemic immunotherapy with a lipid-based nanoparticle platform (CMP) carrying Mn2+ and STING agonist c-di-AMP (CDA) exhibited robust anti-tumor efficacy in a mouse model of disseminated AML. Moreover, CMP immunotherapy combined with immune checkpoint blockade against cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) elicited robust innate and adaptive immune activation with enhanced cytotoxic potential against AML, leading to extended animal survival after re-challenge with AML. Overall, this CMP combination immunotherapy may be a promising approach against AML and other disseminated cancer.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Nanopartículas , Neoplasias , Camundongos , Adulto , Animais , Humanos , Manganês , Leucemia Mieloide Aguda/tratamento farmacológico , Linfócitos T , Imunoterapia , Imunidade Inata
5.
ACS Appl Mater Interfaces ; 16(14): 17129-17144, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38533538

RESUMO

Immune-cell-derived membranes have garnered significant attention as innovative delivery modalities in cancer immunotherapy for their intrinsic immune-modulating functionalities and superior biocompatibilities. Integrating additional parental cell membranes or synthetic lipid vesicles into cellular vesicles can further potentiate their capacities to perform combinatorial pharmacological activities in activating antitumor immunity, thus providing insights into the potential of hybrid cellular vesicles as versatile delivery vehicles for cancer immunotherapy. Here, we have developed a macrophage-membrane-derived hybrid vesicle that has the dual functions of transporting immunotherapeutic drugs and shaping the polarization of tumor-associated macrophages for cancer immunotherapy. The platform combines M1 macrophage-membrane-derived vesicles with CXCR4-binding-peptide-conjugated liposomes loaded with manganese and doxorubicin. The hybrid nanovesicles exhibited remarkable macrophage-targeting capacity through the CXCR4-binding peptide, resulting in enhanced macrophage polarization to the antitumoral M1 phenotype characterized by proinflammatory cytokine release. The manganese/doxorubicin-loaded hybrid vesicles in the CXCR4-expressing tumor cells evoked potent cancer cytotoxicity, immunogenic cell death of tumor cells, and STING activation. Moreover, cotreatment with manganese and doxorubicin promoted dendritic cell maturation, enabling effective tumor growth inhibition. In murine models of CT26 colon carcinoma and 4T1 breast cancer, intravenous administration of the manganese/doxorubicin-loaded hybrid vesicles elicited robust tumor-suppressing activity at a low dosage without adverse systemic effects. Local administration of hybrid nanovesicles also induced an abscessive effect in a bilateral 4T1 tumor model. This study demonstrates a promising biomimetic manganese/doxorubicin-based hybrid nanovesicle platform for effective cancer immunotherapy tailored to the tumor microenvironment, which may offer an innovative approach to combinatorial immunotherapy.


Assuntos
Neoplasias da Mama , Neoplasias , Humanos , Animais , Camundongos , Feminino , Manganês/farmacologia , Biomimética , Doxorrubicina/uso terapêutico , Macrófagos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Imunoterapia/métodos , Peptídeos/farmacologia , Microambiente Tumoral , Linhagem Celular Tumoral , Receptores CXCR4/metabolismo
6.
J Immunol ; 212(2): 208-215, 2024 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-38166246

RESUMO

The gut microbiota, predominantly residing in the colon, is a complex ecosystem with a pivotal role in the host immune system. Dysbiosis of the gut microbiota has been associated with various diseases, and there is an urgent need to develop new therapeutics that target the microbiome and restore immune functions. This Brief Review discusses emerging therapeutic strategies that focus on oral delivery systems for modulating the gut microbiome. These strategies include genetic engineering of probiotics, probiotic-biomaterial hybrids, dietary fibers, and oral delivery systems for microbial metabolites, antimicrobial peptides, RNA, and antibiotics. Engineered oral formulations have demonstrated promising outcomes in reshaping the gut microbiome and influencing immune responses in preclinical studies. By leveraging these approaches, the interplay between the gut microbiota and the immune system can be harnessed for the development of novel therapeutics against cancer, autoimmune disorders, and allergies.


Assuntos
Doenças Autoimunes , Microbioma Gastrointestinal , Microbiota , Probióticos , Humanos , Sistema Imunitário , Probióticos/uso terapêutico , Disbiose
7.
ACS Nano ; 18(6): 4704-4716, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38288705

RESUMO

Liver fibrosis is a life-threatening and irreversible disease. The fibrosis process is largely driven by hepatic stellate cells (HSCs), which undergo transdifferentiation from an inactivated state to an activated one during persistent liver damage. This activated state is responsible for collagen deposition in liver tissue and is accompanied by increased CD44 expression on the surfaces of HSCs and amplified intracellular oxidative stress, which contributes to the fibrosis process. To address this problem, we have developed a strategy that combines CD44-targeting of activated HSCs with an antioxidative approach. We developed hyaluronic acid-bilirubin nanoparticles (HABNs), composed of endogenous bilirubin, an antioxidant and anti-inflammatory bile acid, and hyaluronic acid, an endogenous CD44-targeting glycosaminoglycan biopolymer. Our findings demonstrate that intravenously administered HABNs effectively targeted the liver, particularly activated HSCs, in fibrotic mice with choline-deficient l-amino acid-defined high-fat diet (CD-HFD)-induced nonalcoholic steatohepatitis (NASH). HABNs were able to inhibit HSC activation and proliferation and collagen production. Furthermore, in a murine CD-HFD-induced NASH fibrosis model, intravenously administered HABNs showed potent fibrotic modulation activity. Our study suggests that HABNs have the potential to serve as a targeted anti-hepatic-fibrosis therapy by modulating activated HSCs via CD44-targeting and antioxidant strategies. This strategy could also be applied to various ROS-related diseases in which CD44-overexpressing cells play a pivotal role.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Ácido Hialurônico/farmacologia , Bilirrubina/farmacologia , Células Estreladas do Fígado/metabolismo , Nanomedicina , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Fígado/metabolismo , Fibrose , Colágeno/metabolismo , Camundongos Endogâmicos C57BL
8.
9.
bioRxiv ; 2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-38014059

RESUMO

Understanding adaptive immunity against SARS-CoV-2 is a major requisite for the development of effective vaccines and treatments for COVID-19. CD4+ T cells play an integral role in this process primarily by generating antiviral cytokines and providing help to antibody-producing B cells. To empower detailed studies of SARS-CoV-2-specific CD4+ T cell responses in mouse models, we comprehensively mapped I-Ab-restricted epitopes for the spike and nucleocapsid proteins of the BA.1 variant of concern via IFNγ ELISpot assay. This was followed by the generation of corresponding peptide:MHCII tetramer reagents to directly stain epitope-specific T cells. Using this rigorous validation strategy, we identified 6 reliably immunogenic epitopes in spike and 3 in nucleocapsid, all of which are conserved in the ancestral Wuhan strain. We also validated a previously identified epitope from Wuhan that is absent in BA.1. These epitopes and tetramers will be invaluable tools for SARS-CoV-2 antigen-specific CD4+ T cell studies in mice.

10.
Adv Drug Deliv Rev ; 203: 115140, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37980949

RESUMO

The high prevalence and rising incidence of autoimmune diseases have become a prominent public health issue. Autoimmune disorders result from the immune system erroneously attacking the body's own healthy cells and tissues, causing persistent inflammation, tissue injury, and impaired organ function. Existing treatments primarily rely on broad immunosuppression, leaving patients vulnerable to infections and necessitating lifelong treatments. To address these unmet needs, an emerging frontier of vaccine development aims to restore immune equilibrium by inducing immune tolerance to autoantigens, offering a potential avenue for a cure rather than mere symptom management. We discuss this burgeoning field of vaccine development against inflammation and autoimmune diseases, with a focus on common autoimmune disorders, including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Vaccine-based strategies provide a new pathway for the future of autoimmune disease therapeutics, heralding a new era in the battle against inflammation and autoimmunity.


Assuntos
Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Vacinas , Humanos , Lúpus Eritematoso Sistêmico/complicações , Autoimunidade , Tolerância Imunológica , Inflamação , Vacinas/uso terapêutico
11.
Nature ; 621(7977): 162-170, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37587342

RESUMO

Certain bacterial strains from the microbiome induce a potent, antigen-specific T cell response1-5. However, the specificity of microbiome-induced T cells has not been explored at the strain level across the gut community. Here, we colonize germ-free mice with complex defined communities (roughly 100 bacterial strains) and profile T cell responses to each strain. The pattern of responses suggests that many T cells in the gut repertoire recognize several bacterial strains from the community. We constructed T cell hybridomas from 92 T cell receptor (TCR) clonotypes; by screening every strain in the community against each hybridoma, we find that nearly all the bacteria-specific TCRs show a one-to-many TCR-to-strain relationship, including 13 abundant TCR clonotypes that each recognize 18 Firmicutes. By screening three pooled bacterial genomic libraries, we discover that these 13 clonotypes share a single target: a conserved substrate-binding protein from an ATP-binding cassette transport system. Peripheral regulatory T cells and T helper 17 cells specific for an epitope from this protein are abundant in community-colonized and specific pathogen-free mice. Our work reveals that T cell recognition of commensals is focused on widely conserved, highly expressed cell-surface antigens, opening the door to new therapeutic strategies in which colonist-specific immune responses are rationally altered or redirected.


Assuntos
Bactérias , Microbioma Gastrointestinal , Linfócitos T , Animais , Camundongos , Antígenos de Superfície/imunologia , Bactérias/classificação , Bactérias/imunologia , Firmicutes/imunologia , Microbioma Gastrointestinal/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Linfócitos T/imunologia , Simbiose/imunologia , Vida Livre de Germes , Receptores de Antígenos de Linfócitos T/imunologia , Hibridomas/citologia , Hibridomas/imunologia , Separação Celular
12.
Nat Commun ; 14(1): 4771, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37553327

RESUMO

Despite significant advances in immune checkpoint blockade (ICB), immunosuppression mediated by tumor-associated myeloid cells (TAMCs) poses a major barrier to cancer immunotherapy. In addition, while immunogenic cell death (ICD) provides a viable approach to inducing anti-tumor immune response, it remains unknown how to effectively trigger ICD while addressing immunosuppressive TAMCs. Here, we show that SC144, a gp130 inhibitor that blocks the IL-6/gp130/STAT3 pathway, induces ICD of tumor cells and polarizes macrophages to M1-phenotype in vitro. However, as SC144 also induces killing of CD8+ T-cells, we sought to deliver SC144 selectively to tumor cells and TAMCs. Toward this goal, we have developed hyaluronic acid-bilirubin nanoparticles (HABN) that accumulate in CD44hi tumor cells and TAMCs. Systemic administration of SC144 loaded in HABN (SC144@HABN) induces apoptosis and ICD of tumor cells, increases the ratio of M1-like to M2-like macrophages, and decreases the frequency of myeloid-derived suppressor cells and CD4+ regulatory T-cells, while promoting anti-tumor CD8+ T-cells. Moreover, SC144@HABN combined with anti-PD-L1 ICB efficiently eliminates MC38 tumors and ICB-resistant 4T1 tumors. Overall, our work demonstrates a therapeutic strategy based on coordinated ICD induction and TAMC modulation and highlights the potential of combination chemoimmunotherapy.


Assuntos
Ácido Hialurônico , Neoplasias , Humanos , Ácido Hialurônico/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Nanomedicina , Bilirrubina , Receptor gp130 de Citocina , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Imunoterapia , Microambiente Tumoral , Linhagem Celular Tumoral
13.
J Clin Invest ; 133(17)2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37471146

RESUMO

BACKGROUNDAutoimmune diseases often have strong genetic associations with specific HLA-DR alleles. The synovial lesion in chronic inflammatory forms of arthritis shows marked upregulation of HLA-DR molecules, including in postinfectious Lyme arthritis (LA). However, the identity of HLA-DR-presented peptides, and therefore the reasons for these associations, has frequently remained elusive.METHODSUsing immunopeptidomics to detect HLA-DR-presented peptides from synovial tissue, we identified T cell epitopes from 3 extracellular matrix (ECM) proteins in patients with postinfectious LA, identified potential Borreliella burgdorferi-mimic (Bb-mimic) epitopes, and characterized T and B cell responses to these peptides or proteins.RESULTSOf 24 postinfectious LA patients, 58% had CD4+ T cell responses to at least 1 epitope of 3 ECM proteins, fibronectin-1, laminin B2, and/or collagen Vα1, and 17% of 52 such patients had antibody responses to at least 1 of these proteins. Patients with autoreactive T cell responses had significantly increased frequencies of HLA-DRB1*04 or -DRB1*1501 alleles and more prolonged arthritis. When tetramer reagents were loaded with ECM or corresponding Bb-mimic peptides, binding was only with the autoreactive T cells. A high percentage of ECM-autoreactive CD4+ T cells in synovial fluid were T-bet-expressing Th1 cells, a small percentage were RoRγt-expressing Th17 cells, and a minimal percentage were FoxP3-expressing Tregs.CONCLUSIONAutoreactive, proinflammatory CD4+ T cells and autoantibodies develop to ECM proteins in a subgroup of postinfectious LA patients who have specific HLA-DR alleles. Rather than the traditional molecular mimicry model, we propose that epitope spreading provides the best explanation for this example of infection-induced autoimmunity.FUNDINGSupported by National Institute of Allergy and Infectious Diseases R01-AI101175, R01-AI144365, and F32-AI125764; National Institute of Arthritis and Musculoskeletal and Skin Diseases K01-AR062098 and T32-AR007258; NIH grants P41-GM104603, R24-GM134210, S10-RR020946, S10-OD010724, S10-OD021651, and S10-OD021728; and the G. Harold and Leila Y. Mathers Foundation, the Eshe Fund, and the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital.


Assuntos
Artrite , Borrelia burgdorferi , Doença de Lyme , Humanos , Autoimunidade , Proteínas da Matriz Extracelular , Cadeias HLA-DRB1 , Peptídeos , Epitopos de Linfócito T
14.
Cell Rep ; 42(8): 112839, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37471223

RESUMO

Self-antigen-specific T cells are prevalent in the mature adaptive immune system but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may allow these T cells to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self-antigen under highly stimulatory conditions, we use peptide:major histocompatibility complex (MHC) class II tetramers to track the behavior of endogenous CD4+ T cells with specificity to a lung-expressed self-antigen in mouse models of immune-mediated lung injury. Acute injury results in the exclusive expansion of CD4+ regulatory T cells (Tregs) that is dependent on self-antigen recognition and interleukin-2 (IL-2). Conversely, conventional CD4+ T cells of the same self-antigen specificity remain unresponsive even following Treg ablation. Thus, the self-antigen-specific CD4+ T cell repertoire is poised to serve a regulatory function during acute tissue damage to limit further damage and the possibility of autoimmunity.


Assuntos
Lesão Pulmonar , Linfócitos T Reguladores , Camundongos , Animais , Autoantígenos , Antígenos de Histocompatibilidade Classe II , Autoimunidade , Fatores de Transcrição Forkhead
16.
J Control Release ; 357: 417-421, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37001564

RESUMO

Stimulator of interferon genes (STING) pathway is the key innate immune pathway involving in cancer immunity. Emerging new molecules and drug delivery systems have made systemic STING agonist immunotherapy possible and demonstrated efficient tumor eradication in preclinical studies. In this perspective, we will discuss the potential mechanisms of STING agonism as a multifaceted anti-cancer therapy and the pharmacological challenges associated with systemic delivery of STING agonists on the level of organs, tissues, cells, and intracellular compartments. We will present and discuss drug delivery strategies to address these challenges. New advances in the field can unlock the promise of systemic STING agonist as effective and safe cancer immunotherapy.


Assuntos
Proteínas de Membrana , Neoplasias , Humanos , Imunoterapia , Proteínas de Membrana/agonistas , Neoplasias/tratamento farmacológico , Transdução de Sinais
17.
J Control Release ; 357: 84-93, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36948420

RESUMO

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the production of type-I interferons and other proinflammatory cytokines from dendritic cells. MnOx@HMSN(CDA) carrying cancer neoantigens elicited robust antitumor T-cell immunity with therapeutic efficacy in two different murine tumor models. Furthermore, MnOx@HMSN(CDA) loaded with SARS-CoV-2 antigen achieved strong and durable (up to one year) humoral immune responses with neutralizing capability. These results demonstrate that MnOx@HMSN(CDA) is a versatile nanoplatform for vaccine applications.


Assuntos
COVID-19 , Neuropatia Hereditária Motora e Sensorial , Nanopartículas , Vacinas , Humanos , Animais , Camundongos , Manganês , Dióxido de Silício , COVID-19/prevenção & controle , SARS-CoV-2 , Imunoterapia
18.
Cell Rep ; 42(4): 112303, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-36952341

RESUMO

Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show dampened responses to STING stimulation and are more suppressive of T cell activation. In agreement, obese hosts exhibited increased tumor burden and lower responsiveness to STING agonist. As a mechanism, saturated fatty acids induce the expression of NLRC3, depletion of which results in a T cell inflamed tumor microenvironment and IFN-I-dependent tumor control.


Assuntos
Neoplasias de Cabeça e Pescoço , Interferon Tipo I , Camundongos , Animais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Ácidos Graxos , Interferon Tipo I/metabolismo , Células Mieloides/metabolismo , Microambiente Tumoral
19.
bioRxiv ; 2023 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-36798259

RESUMO

Self antigen-specific T cells are prevalent in the mature adaptive immune system, but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may provide these T cells with an opportunity to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self antigen under highly stimulatory conditions, we used peptide:MHCII tetramers to track the behavior of endogenous CD4 + T cells with specificity to a lung-expressed self antigen in mouse models of immune-mediated lung injury. Acute injury resulted in the exclusive expansion of regulatory T cells (Tregs) that was dependent on self antigen recognition and IL-2. Conversely, conventional T cells of the same self antigen specificity remained unresponsive, even following Treg ablation. Thus, the self antigen-specific T cell repertoire is poised to serve a regulatory function during acute tissue damage to limit further damage and the possibility of autoimmunity.

20.
Nat Biomed Eng ; 7(1): 72-84, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36564626

RESUMO

The effectivity of cancer immunotherapies is hindered by immunosuppressive tumour microenvironments that are poorly infiltrated by effector T cells and natural killer cells. In infection and autoimmune disease, the recruitment and activation of effector immune cells is coordinated by pro-inflammatory T helper 17 (TH17) cells. Here we show that pathogen-mimicking hollow nanoparticles displaying mannan (a polysaccharide that activates TH17 cells in microbial cell walls) limit the fraction of regulatory T cells and induce TH17-cell-mediated anti-tumour responses. The nanoparticles activate the pattern-recognition receptor Dectin-2 and Toll-like receptor 4 in dendritic cells, and promote the differentiation of CD4+ T cells into the TH17 phenotype. In mice, intra-tumoural administration of the nanoparticles decreased the fraction of regulatory T cells in the tumour while markedly increasing the fractions of TH17 cells (and the levels of TH17-cell-associated cytokines), CD8+ T cells, natural killer cells and M1-like macrophages. The anti-tumoural activity of the effector cells was amplified by an agonistic antibody against the co-stimulatory receptor OX40 in multiple mouse models. Nanomaterials that induce TH17-cell-mediated immune responses may have therapeutic potential.


Assuntos
Linfócitos T CD8-Positivos , Nanopartículas , Animais , Camundongos , Diferenciação Celular , Citocinas , Linfócitos T Reguladores , Células Th17/imunologia
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