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1.
Respir Res ; 25(1): 240, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867225

RESUMO

BACKGROUND: Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein. METHODS: Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry. RESULTS: Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls. CONCLUSION: Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH.


Assuntos
Infecções por HIV , Humanos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Feminino , Pessoa de Meia-Idade , Adulto , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/metabolismo , Fumar/efeitos adversos , Líquido da Lavagem Broncoalveolar/imunologia , Antirretrovirais/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Pulmão/imunologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo
2.
Immunity ; 57(6): 1187-1189, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38865963

RESUMO

A major barrier to antitumor immunity in solid tumors is T cell exclusion. In this issue of Immunity, De Sanctis et al.1 elucidate how CLDN18 on pancreatic and lung cancer cells enhances infiltration, immunological synapse formation, and activation of cytotoxic T lymphocytes.


Assuntos
Claudinas , Humanos , Claudinas/metabolismo , Claudinas/imunologia , Claudinas/genética , Neoplasias/imunologia , Animais , Linfócitos T Citotóxicos/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pulmonares/imunologia , Ativação Linfocitária/imunologia , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/metabolismo
3.
Front Immunol ; 15: 1392535, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38846935

RESUMO

The pivotal role of Granzyme B (GzmB) in immune responses, initially tied to cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, has extended across diverse cell types and disease models. A number of studies have challenged conventional notions, revealing GzmB activity beyond apoptosis, impacting autoimmune diseases, inflammatory disorders, cancer, and neurotoxicity. Notably, the diverse functions of GzmB unfold through Perforin-dependent and Perforin-independent mechanisms, offering clinical implications and therapeutic insights. This review underscores the multifaceted roles of GzmB, spanning immunological and pathological contexts, which call for further investigations to pave the way for innovative targeted therapies.


Assuntos
Granzimas , Células Matadoras Naturais , Perforina , Linfócitos T Citotóxicos , Granzimas/metabolismo , Humanos , Perforina/metabolismo , Animais , Linfócitos T Citotóxicos/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Neoplasias/imunologia , Neoplasias/terapia
4.
Exp Oncol ; 46(1): 30-37, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38852055

RESUMO

AIM: To study the activity of antitumor immunity effectors and to analyze possible mechanisms of peritoneal Mph M1/M2 repolarization of Balb/c mice under the influence of lectin from B. subtilis IMV B-7724 in the dynamics of the model tumor growth. MATERIALS AND METHODS: Studies were performed on Balb/c mice; Ehrlich adenocarcinoma (АСЕ) was used as an experimental tumor. Lectin from B. subtilis IMV B-7724 was administered to ACE-bearing mice at a dose of 1 mg/kg of body weight, 10 times. Immunological testing was performed on days 21 and 28 after tumor grafting. The functional activity of peritoneal macrophages (Mph), natural killer (NK) cells, cytotoxic lymphocytes (CTL), and cytokine levels (IFN-γ, IL-4) were studied by the standard methods. mRNA expression levels of transcription factors STAT-1, STAT-6, IRF5, and IRF4 in Mph were evaluated. RESULTS: The administration of lectin from B. subtilis IMV B-7724 to mice with solid ACE led to the preservation of the initial functional state of peritoneal Mph M1 during the experiment. The bacterial lectin ensured the preservation of the cytotoxic activity of CD8+ T-lymphocytes and a significant (p < 0.05) increase in the NK activity (by 2.7 times compared to the intact animals and by 12.9 times compared to the untreated mice). A strong positive correlation was noted between the levels of the functional activity of Mph and CD8+ T-lymphocytes of animals with tumors and the indices of the antitumor effectiveness of bacterial lectin. The indirect polarization of Mph was evidenced by a strong positive correlation between the level of the NO/Arg ratio (which characterizes the direction of Mph polarization) and the cytotoxic activity of CD8+ T-lymphocytes, NK cells, and the expression of STAT1/STAT6 (the 21st day) and IRF5/IRF4 (the 28th day). CONCLUSION: In ACE-bearing mice, repolarization of the peritoneal Mph toward M1 can occur not only due to the direct action of bacterial lectin on the cellular receptors but also with the involvement of other effectors of antitumor immunity (NK cells, T-lymphocytes). The transcription factors of the STAT and IRF signaling pathways are involved in the polarization process.


Assuntos
Células Matadoras Naturais , Macrófagos Peritoneais , Camundongos Endogâmicos BALB C , Animais , Camundongos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Carcinoma de Ehrlich/imunologia , Carcinoma de Ehrlich/patologia , Carcinoma de Ehrlich/metabolismo , Bacillus subtilis , Citocinas/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo
5.
Chaos ; 34(5)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38809906

RESUMO

A time-delayed virus dynamic model is proposed with general monotonic incidence, different nonlinear CTL (cytotoxic T lymphocyte) responses [CTL elimination function pyg1(z) and CTL stimulation function cyg2(z)], and immune impairment. Indeed, the different CTL responses pose challenges in obtaining the dissipativeness of the model. By constructing appropriate Lyapunov functionals with some detailed analysis techniques, the global stability results of all equilibria of the model are obtained. By the way, we point out that the partial derivative fv(x,0) is increasing (but not necessarily strictly) in x>0 for the general monotonic incidence f(x,v). However, some papers defaulted that the partial derivative was strictly increasing. Our main results show that if the basic reproduction number R0≤1, the infection-free equilibrium E0 is globally asymptotically stable (GAS); if CTL stimulation function cyg2(z)=0 for z=0 and the CTL threshold parameter R1≤1

Assuntos
Linfócitos T Citotóxicos , Linfócitos T Citotóxicos/imunologia , Humanos , Fatores de Tempo , Vírus/imunologia , Viroses/imunologia , Modelos Imunológicos , Modelos Biológicos
7.
Oncoimmunology ; 13(1): 2358590, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38812569

RESUMO

Chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic success in hematological malignancies. Yet, their efficacy against solid tumors remains constrained due to inadequate infiltration of cytotoxic T and CAR-T cells in the tumor microenvironment (TME), a factor correlated with poor prognosis in patients with solid tumors. To overcome this limitation, we engineered CAR-T cells to secrete CXCL10 and IL15 (10 × 15 CAR-T), which sustain T cell viability and enhance their recruitment, thereby amplifying the long-term cytotoxic capacity of CAR-T cells in vitro. In a xenograft model employing NUGC4-T21 cells, mice receiving 10 × 15 CAR-T cells showed superior tumor reduction and extended survival rates compared to those treated with second-generation CAR-T cells. Histopathological evaluations indicated a pronounced increase in cytotoxic T cell accumulation in the TME post 10 × 15 CAR-T cell treatment. Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors.


Assuntos
Quimiocina CXCL10 , Imunoterapia Adotiva , Interleucina-15 , Receptores de Antígenos Quiméricos , Neoplasias Gástricas , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Humanos , Camundongos , Interleucina-15/genética , Interleucina-15/metabolismo , Imunoterapia Adotiva/métodos , Microambiente Tumoral/imunologia , Linhagem Celular Tumoral , Linfócitos T Citotóxicos/imunologia , Sobrevivência Celular , Feminino
8.
Front Immunol ; 15: 1362621, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38812512

RESUMO

Introduction: HIV-1 infection may produce a detrimental effect on the immune response. Early start of antiretroviral therapy (ART) is recommended to preserve the integrity of the immune system. In fact, people with HIV (PWH) and normal CD4/CD8 ratio appear not to be more susceptible to severe forms of COVID-19 than the general population and they usually present a good seroconversion rate in response to vaccination against SARS-CoV-2. However, few studies have fully characterized the development of cytotoxic immune populations in response to COVID-19 vaccination in these individuals. Methods: In this study, we recruited PWH with median time of HIV-1 infection of 6 years, median CD4/CD8 ratio of 1.0, good adherence to ART, persistently undetectable viral load, and negative serology against SARS-CoV-2, who then received the complete vaccination schedule against COVID-19. Blood samples were taken before vaccination against COVID-19 and one month after receiving the complete vaccination schedule. Results: PWH produced high levels of IgG against SARS-CoV-2 in response to vaccination that were comparable to healthy donors, with a significantly higher neutralization capacity. Interestingly, the cytotoxic activity of PBMCs from PWH against SARS-CoV-2-infected cells was higher than healthy donors before receiving the vaccination schedule, pointing out the pre-existence of activated cell populations with likely unspecific antiviral activity. The characterization of these cytotoxic cell populations revealed high levels of Tgd cells with degranulation capacity against SARS-CoV-2-infected cells. In response to vaccination, the degranulation capacity of CD8+ T cells also increased in PWH but not in healthy donors. Discussion: The full vaccination schedule against COVID-19 did not modify the ability to respond against HIV-1-infected cells in PWH and these individuals did not show more susceptibility to breakthrough infection with SARS-CoV-2 than healthy donors after 12 months of follow-up. These results revealed the development of protective cell populations with broad-spectrum antiviral activity in PWH with normal CD4/CD8 ratio and confirmed the importance of early ART and treatment adherence to avoid immune dysfunctions.


Assuntos
Relação CD4-CD8 , COVID-19 , Infecções por HIV , SARS-CoV-2 , Humanos , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Vacinas contra COVID-19/imunologia , Linfócitos T CD8-Positivos/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , HIV-1/imunologia , Citotoxicidade Imunológica , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinação
9.
Yakugaku Zasshi ; 144(5): 475-481, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38692920

RESUMO

Zinc is one of the essential trace elements, and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism is not fully understood. Therefore, we focused our research on tumor immunity to elucidate the effect of zinc on colorectal cancer and its mechanisms. Mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) to develop colorectal cancer, then the relationship between zinc content in the diet and the number and area of tumors in the colon was observed. The number of tumors in the colon was significantly higher in the no-zinc-added diet group compared to the normal zinc intake group, and about half the number in the high-zinc-intake group compared to the normal-zinc-intake group. In T-cell-deficient mice, the number of tumors in the high-zinc-intake group was similar to that in the normal-zinc-intake group, suggesting that the inhibitory effect of zinc was dependent on T cells. Furthermore, we found that the amount of granzyme B transcript released by cytotoxic T cells upon antigen stimulation was significantly increased by the addition of zinc. We also showed that granzyme B transcriptional activation by zinc addition was dependent on calcineurin activity. Collectively, we have shown that zinc exerts its tumor-suppressive effect by acting on cytotoxic T cells, the center of cellular immunity, and that it increases the transcription of granzyme B, one of the key molecules involved in tumor immunity. In this symposium, we would like to introduce our latest data on the relationship between zinc and tumor immunity.


Assuntos
Neoplasias Colorretais , Imunidade Celular , Zinco , Animais , Humanos , Camundongos , Azoximetano , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/prevenção & controle , Modelos Animais de Doenças , Granzimas/metabolismo , Linfócitos T Citotóxicos/imunologia
10.
ACS Nano ; 18(20): 13226-13240, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38712706

RESUMO

Oncogene activation and epigenome dysregulation drive tumor initiation and progression, contributing to tumor immune evasion and compromising the clinical response to immunotherapy. Epigenetic immunotherapy represents a promising paradigm in conquering cancer immunosuppression, whereas few relevant drug combination and delivery strategies emerge in the clinic. This study presents a well-designed triune nanomodulator, termed ROCA, which demonstrates robust capabilities in tumor epigenetic modulation and immune microenvironment reprogramming for cancer epigenetic immunotherapy. The nanomodulator is engineered from a nanoscale framework with epigenetic modulation and cascaded catalytic activity, which self-assembles into a nanoaggregate with tumor targeting polypeptide decoration that enables loading of the immunogenic cell death (ICD)-inducing agent. The nanomodulator releases active factors specifically triggered in the tumor microenvironment, represses oncogene expression, and initiates the type 1 T helper (TH1) cell chemokine axis by reversing DNA hypermethylation. This process, together with ICD induction, fundamentally reprograms the tumor microenvironment and significantly enhances the rejuvenation of exhausted cytotoxic T lymphocytes (CTLs, CD8+ T cells), which synergizes with the anti-PD-L1 immune checkpoint blockade and results in a boosted antitumor immune response. Furthermore, this strategy establishes long-term immune memory and effectively prevents orthotopic colon cancer relapse. Therefore, the nanomodulator holds promise as a standalone epigenetic immunotherapy agent or as part of a combination therapy with immune checkpoint inhibitors in preclinical cancer models, broadening the array of combinatorial strategies in cancer immunotherapy.


Assuntos
Epigênese Genética , Imunoterapia , Linfócitos T Citotóxicos , Microambiente Tumoral , Animais , Epigênese Genética/efeitos dos fármacos , Camundongos , Linfócitos T Citotóxicos/imunologia , Humanos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Nanopartículas/química , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Neoplasias/imunologia
11.
Biochem Biophys Res Commun ; 718: 150058, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-38729076

RESUMO

The therapeutic efficacy of radiotherapy (RT) is primarily driven by two factors: biophysical DNA damage in cancer cells and radiation-induced anti-tumor immunity. However, Anti-tumor immune responses between X-ray RT (XRT) and carbon-ion RT (CIRT) remain unclear. In this study, we, employed mouse models to assess the immunological contribution, especially cytotoxic T-lymphocyte (CTL)-mediated immunity, to the therapeutic effectiveness of XRT and CIRT in shrinking tumors. We irradiated mouse intradermal tumors of B16F10-ovalbumin (OVA) mouse melanoma cells and 3LL-OVA mouse lung cancer cells with carbon-ion beams or X-rays in the presence or absence of CTLs. CTL removal was performed by administration of anti-CD8 monoclonal antibody (mAb) in mice. Based on tumor growth delay, we determined the tumor growth and regression curves. The enhancement ratio (ER) of the slope of regression lines in the presence of CTLs, relative to the absence of CTLs, indicates the dependency of RT on CTLs for shrinking mouse tumors, and the biological effectiveness (RBE) of CIRT relative to XRT were calculated. Tumor growth curves revealed that the elimination of CD8+ CTLs by administrating anti-CD8 mAb accelerated tumor growth compared to the presence of CTLs in both RTs. The ERs were larger in CIRT compared to XRT in the B16F10-OVA tumor models, but not in the 3LL-OVA models, suggesting a greater contribution of CTL-mediated anti-tumor immunity to tumor reduction in CIRT compared to XRT in the B16F10-OVA tumor model. In addition, the RBE values for both models were larger in the presence of CTLs compared to models without CTLs, suggesting that CIRT may utilize CTL-mediated anti-tumor immunity more than X-ray. The findings from this study suggest that although immunological contribution to therapeutic efficacy may vary depending on the type of tumor cell, CIRT utilizes CTL-mediated immunity to a greater extent compared to XRT.


Assuntos
Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos , Animais , Linfócitos T Citotóxicos/imunologia , Camundongos , Linhagem Celular Tumoral , Melanoma Experimental/imunologia , Melanoma Experimental/radioterapia , Melanoma Experimental/terapia , Melanoma Experimental/patologia , Radioterapia com Íons Pesados/métodos , Terapia por Raios X , Feminino , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia
12.
Immunity ; 57(6): 1378-1393.e14, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38749447

RESUMO

Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors. In human pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer, CLDN18 expression positively correlated with more differentiated histology and favorable prognosis. CLDN18 on the cell surface promoted accrual of cytotoxic T lymphocytes (CTLs), facilitating direct CTL contacts with tumor cells by driving the mobilization of the adhesion protein ALCAM to the lipid rafts of the tumor cell membrane through actin. This process favored the formation of robust immunological synapses (ISs) between CTLs and CLDN18-positive cancer cells, resulting in increased T cell activation. Our data reveal an immune role for CLDN18 in orchestrating T cell infiltration and shaping the tumor immune contexture.


Assuntos
Carcinoma Ductal Pancreático , Claudinas , Ativação Linfocitária , Neoplasias Pancreáticas , Linfócitos T Citotóxicos , Humanos , Claudinas/metabolismo , Claudinas/genética , Animais , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Camundongos , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Linfócitos T Citotóxicos/imunologia , Ativação Linfocitária/imunologia , Linhagem Celular Tumoral , Sinapses Imunológicas/metabolismo , Sinapses Imunológicas/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BL , Microdomínios da Membrana/metabolismo , Microdomínios da Membrana/imunologia , Microambiente Tumoral/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia
13.
Biochim Biophys Acta Mol Basis Dis ; 1870(6): 167219, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38734321

RESUMO

Chronic infections induce CD4+ T-cells with cytotoxic functions (CD4 CTLs); at present, it is still unknown whether latent tuberculosis (LTB) and active tuberculosis (ATB) induce CD4 CTLs. Plasma and cells from four patient groups-uninfected contact (UC), LTB, and ATB (divided as sensitive [DS-TB]- or resistant [DR-TB]-drug)-were evaluated by flow cytometry, q-PCR, and proteomics. The data showed that ATB patients had an increased frequency of CD4+ T-cells and a decreased frequency of CD8+ T-cells. The latter displays an exhausted-like profile characterized by CD39, CD279, and TIM-3 expression. ATB had a high frequency of CD4 + perforin+ cells, suggesting a CD4 CTL profile. The expression (at the transcriptional level) of granzyme A, granzyme B, granulysin, and perforin, as well as the genes T-bet (Tbx21) and NKG2D (Klrk1), in enriched CD4+ T-cells, confirmed the cytotoxic signature of CD4+ T-cells during ATB (which was stronger in DS-TB than in DR-TB). Moreover, proteomic analysis revealed the presence of HSP70 (in DS-TB) and annexin A5 (in DR-TB), which are molecules that have been associated with favoring the CD4 CTL profile. Finally, we found that lipids from Mycobacterium tuberculosis increased the presence of CD4 CTLs in DR-TB patients. Our data suggest that ATB is characterized by exhausted-like CD8+ T-cells, which, together with a specific microenvironment, favor the presence of CD4 CTLs.


Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Granzimas , Receptor Celular 2 do Vírus da Hepatite A , Perforina , Tuberculose , Humanos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Masculino , Granzimas/metabolismo , Granzimas/genética , Granzimas/imunologia , Perforina/metabolismo , Perforina/genética , Perforina/imunologia , Adulto , Feminino , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Mycobacterium tuberculosis/imunologia , Proteínas com Domínio T/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Antígenos CD/metabolismo , Antígenos CD/imunologia , Antígenos CD/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Proteômica/métodos , Antígenos de Diferenciação de Linfócitos T , Apirase
14.
Exp Cell Res ; 439(2): 114099, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38802035

RESUMO

Gastric cancer is histologically classified into the intestinal subtype, which forms tubular structures, and the aggressive diffuse subtype, characterized by rapid invasion and poor prognosis. The variety and quantity of miRNA isoforms between different histological subtypes of gastric cancer were unknown. Through systematic filtering, we found that more diverse miR-30a-5p isoforms was present in the diffuse subtype of gastric cancer, and was associated with patients' worse survival independent of tumor stage based on the TCGA miRNA-seq data. Among all nine isoforms of miR-30a-5p, miR-30a-5p -1|1 was more abundant than the archetype of miR-30a-5p. Higher expression of miR-30a-5p -1|1 was observed in patients with advanced tumor stage and poor survival. Furthermore, miR-30a-5p -1|1 could promote the metastasis of gastric cancer cells both in vitro and in vivo by down-regulating TMEM66. In clinical samples, decreased expression of TMEM66 was characteristic of gastric cancer, and the low level of TMEM66 correlated with deceased CD8 positive cells in the tumor microenvironment probably due to decreased cytokines production. In conclusion, the variety of miR-30a-5p isoforms correlates with worse survival in gastric cancer patients. Moreover, miR-30a-5p -1|1 could promote gastric cancer metastasis by inhibiting TMEM66 and the infiltration of intratumoral CD8 positive cells.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana , MicroRNAs , Neoplasias Gástricas , Linfócitos T Citotóxicos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Animais , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Camundongos , Microambiente Tumoral/genética , Progressão da Doença , Linhagem Celular Tumoral , Camundongos Nus , Masculino , Feminino , Prognóstico , Proliferação de Células/genética
15.
Nat Biomed Eng ; 8(5): 499-512, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38693431

RESUMO

Bispecific T-cell engagers (BiTEs) bring together tumour cells and cytotoxic T cells by binding to specific cell-surface tumour antigens and T-cell receptors, and have been clinically successful for the treatment of B-cell malignancies. Here we show that a BiTE-sialidase fusion protein enhances the susceptibility of solid tumours to BiTE-mediated cytolysis of tumour cells via targeted desialylation-that is, the removal of terminal sialic acid residues on glycans-at the BiTE-induced T-cell-tumour-cell interface. In xenograft and syngeneic mouse models of leukaemia and of melanoma and breast cancer, and compared with the parental BiTE molecules, targeted desialylation via the BiTE-sialidase fusion proteins enhanced the formation of immunological synapses, T-cell activation and T-cell-mediated tumour-cell cytolysis in the presence of the target antigen. The targeted desialylation of tumour cells may enhance the potency of therapies relying on T-cell engagers.


Assuntos
Neuraminidase , Animais , Neuraminidase/metabolismo , Humanos , Camundongos , Linhagem Celular Tumoral , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/genética , Linfócitos T/imunologia , Feminino , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , Ativação Linfocitária , Ácido N-Acetilneuramínico/metabolismo , Ácido N-Acetilneuramínico/química , Ensaios Antitumorais Modelo de Xenoenxerto , Linfócitos T Citotóxicos/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia
16.
Exp Cell Res ; 439(1): 114073, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38704079

RESUMO

Determining the appropriate source of antigens for optimal antigen presentation to T cells is a major challenge in designing dendritic cell (DC) -based therapeutic strategies against hepatocellular carcinoma (HCC). Tumor-derived exosomes (Tex) express a wide range of tumor antigens, making them a promising source of antigens for DC vaccines. As reported, the exosomes secreted by tumor cells can inhibit the antitumor function of immune cells. In this study, we transfected hepatocellular carcinoma cells with Rab27a to enhance the yield of exosomes, which were characterized using transmission electron microscopy and Western blot analysis. We found that Tex secreted by overexpressing Rab27a Hepatocellular carcinoma cell lines pulsed DC is beneficial for the differentiation and maturation of DCs but inhibits the secretion of the IL-12 cytokine. Consequently, we developed a complementary immunotherapy approach by using Tex as an antigen loaded onto DCs, in combination with the cytokine IL-12 to induce antigen-specific cytotoxic T lymphocytes (CTLs). The results indicated that the combination of DC-Tex and IL-12 was more effective in stimulating T lymphocyte proliferation, releasing IFN-γ, and enhancing cytotoxicity compared to using exosomes or IL-12 alone. Additionally, the inclusion of IL-12 also compensated for the reduced IL-2 secretion by DCs caused by Tex. Moreover, in a BALB/c nude mice model of hepatocellular carcinoma, CTLs induced by DC-Tex combined with IL-12 maximized the tumor-specific T-cell immune effect and suppressed tumor growth. Thus, Tex provides a novel and promising source of antigens, with cytokines compensating for the shortcomings of Tex as a tumor antigen. This work helps to clarify the role of exosomes in tumor immunotherapy and may offer a safe and effective prospective strategy for the clinical application of exosome-based cellular immunotherapy.


Assuntos
Carcinoma Hepatocelular , Células Dendríticas , Exossomos , Interleucina-12 , Neoplasias Hepáticas , Proteínas rab27 de Ligação ao GTP , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Exossomos/metabolismo , Animais , Interleucina-12/metabolismo , Interleucina-12/genética , Proteínas rab27 de Ligação ao GTP/metabolismo , Proteínas rab27 de Ligação ao GTP/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Camundongos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Humanos , Linhagem Celular Tumoral , Proliferação de Células , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Camundongos Endogâmicos BALB C , Imunoterapia/métodos
17.
Vaccine ; 42(18): 3899-3915, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38719691

RESUMO

Scrub typhus, a potentially life-threatening infectious disease, is attributed to bacteria Orientia tsutsugamushi (O. tsutsugamushi). The transmission of this illness to humans occurs through the bite of infected chiggers, which are the larval forms of mites belonging to the genus Leptotrombidium. In this research, we developed a subunit vaccine specifically designed to target outer membrane proteins. Immunodominant cytotoxic T-lymphocytes (CTLs), B- lymphocytes (BCLs), and major histocompatibility complex (MHC)- II epitopes were identified using machine learning and bioinformatics approaches. These epitopes were arranged in different combinations with the help of suitable linkers like AAY, KK, GPGPG and adjuvant (cholera toxin B) that resulted in a vaccine construct. Physiochemical properties were assessed, where the predicted solubility (0.571) was higher than threshold value. Tertiary structure was predicted using I-TASSER web server and evaluated using Ramachandran plot (94 % residues in most favourable region) and z-score (-6.04), which had shown the structure to have good stability and residue arrangement. Molecular docking with immune receptors, Toll-like receptor (TLR)-2 and -4 showed good residue interaction with 13 and 5 hydrogen bonds respectively. Molecular dynamics simulations of receptor-ligand complex provided the idea about the strong interaction having 1.524751 × 10-5 eigenvalue. Amino acid sequence of vaccine was converted to nucleotide sequence and underwent codon optimization. The optimized codon sequence was used for in-silico cloning, which provided idea about the possibility of synthesis of vaccine using E. coli as host. Overall, this study provided a promising blueprint for a scrub typhus vaccine, although experimental validation is needed for confirmation. Furthermore, it is crucial to acknowledge that while bioinformatics provides valuable insights, in-vitro and in-vivo studies are imperative for a comprehensive evaluation of vaccine candidate. Thus, the integration of computational predictions with empirical research is essential to validate the efficacy, safety, and real-world applicability of the designed vaccine against Scrub Typhus. Nevertheless, the findings are good to carry forward for in-vitro and in-vivo investigations.


Assuntos
Epitopos de Linfócito B , Epitopos de Linfócito T , Orientia tsutsugamushi , Tifo por Ácaros , Vacinas de Subunidades Antigênicas , Tifo por Ácaros/imunologia , Tifo por Ácaros/prevenção & controle , Orientia tsutsugamushi/imunologia , Humanos , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Simulação de Acoplamento Molecular , Vacinas Bacterianas/imunologia , Simulação por Computador , Biologia Computacional/métodos , Linfócitos T Citotóxicos/imunologia , Aprendizado de Máquina , Linfócitos B/imunologia , Receptor 2 Toll-Like/imunologia
18.
Int J Biol Macromol ; 269(Pt 2): 132177, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38729484

RESUMO

Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.


Assuntos
Vacinas Anticâncer , Ácido Hialurônico , Hidrogéis , Indóis , Nanopartículas , Polímeros , Ácido Hialurônico/química , Polímeros/química , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Indóis/química , Indóis/farmacologia , Animais , Camundongos , Hidrogéis/química , Nanopartículas/química , Humanos , Imiquimode/química , Imiquimode/farmacologia , Células Dendríticas/imunologia , Vacinação , Linhagem Celular Tumoral , Imunoterapia/métodos , Reagentes de Ligações Cruzadas/química , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos
19.
J Math Biol ; 89(1): 6, 2024 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-38762831

RESUMO

Multiple infections enable the recombination of different strains, which may contribute to viral diversity. How multiple infections affect the competition dynamics between the two types of strains, the wild and the immune escape mutant, remains poorly understood. This study develops a novel mathematical model that includes the two strains, two modes of viral infection, and multiple infections. For the representative double-infection case, the reproductive numbers are derived and global stabilities of equilibria are obtained via the Lyapunov direct method and theory of limiting systems. Numerical simulations indicate similar viral dynamics regardless of multiplicities of infections though the competition between the two strains would be the fiercest in the case of quadruple infections. Through sensitivity analysis, we evaluate the effect of parameters on the set-point viral loads in the presence and absence of multiple infections. The model with multiple infections predict that there exists a threshold for cytotoxic T lymphocytes (CTLs) to minimize the overall viral load. Weak or strong CTLs immune response can result in high overall viral load. If the strength of CTLs maintains at an intermediate level, the fitness cost of the mutant is likely to have a significant impact on the evolutionary dynamics of mutant viruses. We further investigate how multiple infections alter the viral dynamics during the combination antiretroviral therapy (cART). The results show that viral loads may be underestimated during cART if multiple-infection is not taken into account.


Assuntos
Simulação por Computador , Infecções por HIV , Evasão da Resposta Imune , Conceitos Matemáticos , Modelos Biológicos , Linfócitos T Citotóxicos , Carga Viral , Humanos , Infecções por HIV/imunologia , Infecções por HIV/virologia , Infecções por HIV/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Evasão da Resposta Imune/imunologia , Coinfecção/imunologia , Coinfecção/virologia , HIV-1/imunologia , HIV-1/genética , Número Básico de Reprodução/estatística & dados numéricos , Modelos Imunológicos , Mutação
20.
Hum Vaccin Immunother ; 20(1): 2352908, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38780076

RESUMO

Cervical cancer, among the deadliest cancers affecting women globally, primarily arises from persistent infection with high-risk human papillomavirus (HPV). To effectively combat persistent infection and prevent the progression of precancerous lesions into malignancy, a therapeutic HPV vaccine is under development. This study utilized an immunoinformatics approach to predict epitopes of cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) using the E6 and E7 oncoproteins of the HPV16 strain as target antigens. Subsequently, through meticulous selection of T-cell epitopes and other necessary elements, a multi-epitope vaccine was constructed, exhibiting good immunogenic, physicochemical, and structural characteristics. Furthermore, in silico simulations showed that the vaccine not only interacted well with toll-like receptors (TLR2/TLR3/TLR4), but also induced a strong innate and adaptive immune response characterized by elevated Th1-type cytokines, such as interferon-gamma (IFN-γ) and interleukin-2 (IL2). Additionally, our study investigated the effects of different immunization intervals on immune responses, aiming to optimize a time-efficient immunization program. In animal model experiments, the vaccine exhibited robust immunogenic, therapeutic, and prophylactic effects. Administered thrice, it consistently induced the expansion of specific CD4 and CD8 T cells, resulting in substantial cytokines release and increased proliferation of memory T cell subsets in splenic cells. Overall, our findings support the potential of this multi-epitope vaccine in combating HPV16 infection and signify its candidacy for future HPV vaccine development.


Through the stringent selection of T-cell epitopes and other necessary elements, a novel multi-epitope vaccine targeting HPV 16 E6 and E7 oncoproteins was constructed using an immunoinformatics approach.The vaccine designed can induce both cellular and humoral immune responses, encompassing all the required immunogenic, physicochemical, and structural characteristics for an ideal vaccine design. Moreover, it offers decent worldwide coverage.In animal studies, the vaccine demonstrated strong immune responses, including expansion of CD4 and CD8 T cells, cytokine release, and enhanced memory T cell proliferation, resulting in long-term anti-tumor effects, inhibition of tumor growth, and prolonged survival in tumor-bearing mice.The immunological evaluation of the designed vaccine suggests its potential as a novel vaccine candidate against HPV 16.


Assuntos
Epitopos de Linfócito T , Papillomavirus Humano 16 , Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero , Vacinas de DNA , Feminino , Vacinas contra Papillomavirus/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Papillomavirus Humano 16/imunologia , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/imunologia , Epitopos de Linfócito T/imunologia , Animais , Proteínas Oncogênicas Virais/imunologia , Proteínas Oncogênicas Virais/genética , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/virologia , Proteínas E7 de Papillomavirus/imunologia , Camundongos , Humanos , Linfócitos T Citotóxicos/imunologia , Proteínas Repressoras/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Camundongos Endogâmicos C57BL , Interferon gama/metabolismo , Interferon gama/imunologia
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