RESUMEN
PURPOSE: Colorectal cancer (CRC) is one of the top five cancer-related causes of mortality globally. Acquired resistance has hindered the effectiveness of 5-fluorouracil (5-FU), the main chemotherapeutic drug used to treat CRC. Sphingosine kinase 2 (SphK2) may be a cancer treatment target and involved in 5-FU resistance. METHODS: Cell growth was examined using MTT and clone formation assays for SphK2 expression. To identify immune cells in mice, flow cytometry was performed. West blotting demonstrated alterations in cell division and inflammation-related proteins. SphK2 levels and inflammation-related variables were studied using Elisa. RESULTS: Due to SphK2 overexpression, immunosuppression, and 5-FU resistance are caused by the development of myeloid-derived suppressor cells (MDSCs) subsequent to IL-6/STAT3 activation and alterations in the arginase (ARG-1) protein. After therapy, the combination of SphK2 inhibitors and 5-FU can effectively suppress MDSCs while increasing CD4+ and CD8+ T cell infiltration into the tumor microenvironment, lowering tumor burden, and exhibiting a therapeutic impact on CRC. CONCLUSIONS: Our findings suggest that 5-FU treatment combined with simultaneous Spkh2 inhibition by ABC294640 has anti-tumor synergistic effects by influencing multiple effects on tumor cells, T cells, and MDSCs, potentially improving the poor prognosis of colorectal cancer patients.
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Neoplasias Colorrectales , Resistencia a Antineoplásicos , Fluorouracilo , Células Supresoras de Origen Mieloide , Fosfotransferasas (Aceptor de Grupo Alcohol) , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Animales , Ratones , Humanos , Línea Celular Tumoral , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) have immature morphology, relatively weak phagocytic activity, as well as some immunosuppressive functions. The capacity of MDSCs to inhibit T-cell-mediated immunological responses is their most notable functional characteristic. Down-regulating antitumor immune surveillance is one way that the expansion and activation of MDSCs contribute significantly to the occurrence and progression of tumors. Increased levels of MDSCs in patients with chronic hepatitis C virus (HCV) infection could suppress T-cell responses, promoting viral escape and hepatitis progression. This may make HCV-infected individuals more vulnerable to severe infections, hepatic and extra-hepatic tumors, and a diminished capacity to react to immunization. It is still unknown if effective HCV eradication with directly acting antivirals (DAAs) can restore immune functions and immune surveillance capacity. OBJECTIVE: The purpose of this study was to observe the frequency of M-MDSCs (CD33+, CD11b+, and HLA-DR) in patients with a previous history of HCV, 2-3 years after virus eradication using DAA therapy. METHODS: This study was conducted on 110 subjects: fifty-five subjects without liver cirrhosis who were treated with HCV using DAAs and attained SVR for a period of 2-3 years and 55 age- and gender-matched healthy controls. The study was conducted during the period from January to July 2022. Patients were recruited from the National Viral Hepatitis Treatment Unit, Alexandria University Hepatology outpatient clinic, and the Alexandria University Tropical Medicine outpatient clinic. The frequencies of MDSCs (CD33+CD11b + HLA-DR-) by flow cytometry were assessed. RESULTS: Even after the virus had been eradicated for longer than two years, MDSC levels in HCV-treated individuals were found to be considerably higher. In the HCV-treated group, the median number of MDSCs was 5, with an interquartile range (IQR) of 3.79-7.69. In contrast, the median for the control group was 3.1, with an IQR of 1.4-3.2 (PË0.001). CONCLUSION: Successful DAA therapy leads to slow and partial immunological reconstitution, as demonstrated by the failure to attain normal levels of MDSC's 2 years after successful HCV eradication despite the normalization of laboratory parameters as well as the absence of liver fibrosis. The clinical implications of these findings should be thoroughly studied.
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Antivirales , Hepatitis C Crónica , Células Supresoras de Origen Mieloide , Humanos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Antivirales/uso terapéutico , Femenino , Masculino , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/inmunología , Persona de Mediana Edad , Estudios de Casos y Controles , Adulto , Anciano , Citometría de FlujoRESUMEN
Nimodipine, a calcium antagonist, exert beneficial neurovascular protective effects in clinic. Recently, Calcium channel blockers (CCBs) was reported to protect against liver fibrosis in mice, while the exact effects of Nimodipine on liver injury and hepatic fibrosis remain unclear. In this study, we assessed the effect of nimodipine in Thioacetamide (TAA)-induced liver fibrosis mouse model. Then, the collagen deposition and liver inflammation were assessed by HE straining. Also, the frequency and phenotype of NK cells, CD4+T and CD8+T cells and MDSC in liver and spleen were analyzed using flow cytometry. Furthermore, activation and apoptosis of primary Hepatic stellate cells (HSCs) and HSC line LX2 were detected using α-SMA staining and TUNEL assay, respectively. We found that nimodipine administration significantly attenuated liver inflammation and fibrosis. And the increase of the numbers of hepatic NK and NKT cells, a reversed CD4+/CD8+T ratio, and reduced the numbers of MDSC were observed after nimodipine treatment. Furthermore, nimodipine administration significantly decreased α-SMA expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Nimodipine also reduced the proliferation of LX2, and significantly promoted high level of apoptosis in vitro. Moreover, nimodipine downregulated Bcl-2 and Bcl-xl, simultaneously increased expression of JNK, p-JNK, and Caspase-3. Together, nimodipine mediated suppression of growth and fibrogenesis of HSCs may warrant its potential use in the treatment of liver fibrosis.
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Células Estrelladas Hepáticas , Células Asesinas Naturales , Cirrosis Hepática , Hígado , Ratones Endogámicos C57BL , Nimodipina , Tioacetamida , Animales , Nimodipina/farmacología , Nimodipina/uso terapéutico , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/inmunología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Cirrosis Hepática/inmunología , Ratones , Hígado/efectos de los fármacos , Hígado/patología , Hígado/inmunología , Masculino , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Apoptosis/efectos de los fármacos , Humanos , Modelos Animales de Enfermedad , Línea Celular , Microambiente Celular/efectos de los fármacos , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunologíaRESUMEN
Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as reactive oxygen species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon cancer tumors. In vivo studies demonstrated that intratumoral survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon cancer. Depletion of CD8+ T cells could significantly inhibit survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon cancer and provide a new idea for cancer therapy.
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Neoplasias del Colon , Óxidos S-Cíclicos , Ratones Endogámicos BALB C , ARN Mensajero , Factor de Transcripción STAT3 , Survivin , Animales , Survivin/genética , Survivin/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , ARN Mensajero/genética , Neoplasias del Colon/terapia , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Neoplasias del Colon/genética , Óxidos S-Cíclicos/farmacología , Línea Celular Tumoral , Inyecciones Intralesiones , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Ratones , Femenino , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Humanos , Carga Tumoral/efectos de los fármacos , Transducción de SeñalRESUMEN
Invariant natural killer T cell (iNKT) cells produce large amounts of cytokines in response to α-Galactosylceramide (α-GalCer) stimulation. An analog containing two phenyl rings on the acyl chain, C34, was previously found to be more Th1-biased than α-GalCer and triggered greater anticancer activities against breast cancer, melanoma and lung cancer in mice. Since liver is enriched in iNKT cells, we investigated anticancer efficacy of C34 on neuroblastoma with hepatic metastasis. C34 induced Th1-biased cytokine secretions in the liver, significantly suppressed neuroblastoma growth/metastasis and prolonged mouse survival. The anti-tumor efficacy might be attributed to greater expansions of hepatic NKT, NK, CD4+ T, and CD8+ T cells as well as reduction of the number of SSCloGr1intCD11b+ subset of myeloid-derived suppressor cells (MDSCs) in the liver of tumor-bearing mice, as compared to DMSO control group. C34 also upregulated expression of CD1d and CD11c, especially in the SSCloGr1intCD11b+ subset of MDSCs, which might be killed by C34-activated NKT cells, attributing to their reduced number. In addition, C34 also induced expansion of CD4+ T, CD8+ T, and NK cells, which might eliminate neuroblastoma cells. These immune-modulating effects of C34 might act in concert in the local milieu of liver to suppress the tumor growth. Further analysis of database of neuroblastoma revealed that patients with high CD11c expression in the monocytic MDSCs in the tumor had longer survival, suggesting the potential clinical application of C34 for treatment of neuroblastoma.
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Glucolípidos , Neoplasias Hepáticas , Células T Asesinas Naturales , Neuroblastoma , Animales , Neuroblastoma/patología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/inmunología , Células T Asesinas Naturales/efectos de los fármacos , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Línea Celular Tumoral , Ratones , Glucolípidos/farmacología , Humanos , Femenino , Citocinas/metabolismo , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Antineoplásicos/farmacología , Galactosilceramidas/farmacologíaRESUMEN
Cancer immunotherapies are ineffective in nonresponding patients due to absence of immune responses. Here, we identified that dihydroartemisinin (DHA) induced immunogenic cell death (ICD) in hepatocellular carcinoma (HCC), proved by release or surface expose of damage-associated molecular patterns and in vivo protective vaccine activity. Mechanistically, DHA can inhibit cyclin-dependent kinases (CDKs), leading to a buildup of intracellular reactive oxygen species (ROS), which induces immunogenic cell death. In both Hepa1-6 and H22 tumor bearing mice, DHA exerted anti-tumor activity through increasing tumor-infiltrating CD8+ T cells with expression of activation makers (CD25 and CD69), secretion of intracellular cytokines (IFN-γ and TNF-α) and activated dendritic cells expressing MHCâ ¡, CD80 and CD86. In hepa1-6 tumor bearing mice, DHA decreased immunosuppressive myeloid-derived suppressor cells. Furthermore, DHA enhanced the anti-PD-1 antibody and chimeric antigen receptor (CAR) T cell-mediated tumor suppression through recruitment and activation of endogenous CD8+ T cells. Overall, we demonstrated that by inhibiting CDKs, DHA can remodel tumor micro-environment to amplify anti-tumor immune responses in HCC. These findings provide a promising therapy option for HCC patients.
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Artemisininas , Linfocitos T CD8-positivos , Carcinoma Hepatocelular , Quinasas Ciclina-Dependientes , Inmunoterapia , Neoplasias Hepáticas , Ratones Endogámicos C57BL , Microambiente Tumoral , Animales , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Artemisininas/farmacología , Artemisininas/uso terapéutico , Ratones , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/metabolismo , Línea Celular Tumoral , Humanos , Inmunoterapia/métodos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , MasculinoRESUMEN
BACKGROUND: Toll-like receptor 9 (TLR9) agonists induce inflammatory responses that promote the killing of infectious micro-organisms, cancer cells and develop adaptive immune responses. Their ability as immunomodulators to enhance the activity of checkpoint inhibitors (CPI) in treating liver tumors is limited in part by the distinctive biology of intrahepatic myeloid-derived suppressor cells (MDSC) and challenges with tumor-specific therapeutic delivery. We have shown that the regional delivery of type C TLR9 agonist via pressure-enabled drug delivery (PEDD) system improves delivery to the tumor, enhances depletion of MDSCs and overall, stimulates the immune system in combination with or without CPI. Currently, CPIs are delivered intravenously, although there is a growing interest in its subcutaneous (SQ) administration. We compared nelitolimod formerly known as SD-101 administered using PEDD in combination with systemic (Sys) or SQ CPI in murine liver metastases (LM). METHODS: The LM model was developed by injecting MC38-Luc cells via the spleen of 8-12 week old male C57/BL6 mice followed by splenectomy. After a week, fluorescently labeled nelitolimod (10 µg/mouse) was delivered via PEDD and co-administered anti-programmed cell death-1 (α-PD-1) either via Sys or SQ. Tumor burden was monitored by in vivo imaging system. Serum cytokine levels were analyzed by Luminex. Tissues were harvested on Day 3 (D3) or Day 10 (D10) post-PEDD to enrich CD45+ cells and were analyzed via NanoString targeted transcriptomics (D3) or flow cytometry (FC, D10) to interrogate immune cell populations (D10). For NanoString analysis, the innate immune panels were selected, and for FC, MDSCs (CD11b+Gr1+), B cells (B220+), dendritic cells (DC, CD11c+), T (CD3+) cells, and M1-like macrophages (F4/80+CD38+Egr2-) were quantified. RESULTS: Nelitolimod delivered via PEDD resulted in changes in innate and adaptive immune cells within LM, including depletion of liver MDSC and increased M1-like macrophages in the liver, which are supportive of antitumor immunity. While CPI monotherapy failed to control tumor progression, nelitolimod and CPI combination improved LM control, survival and antitumor immunity beyond the nelitolimod monotherapy effect, irrespective of CPI delivery route. CONCLUSION: The SQ route of CPI delivery was equivalent to Sys in combination with nelitolimod, suggesting SQ-CPI may be a rational choice in combination with PEDD of nelitolimod for liver tumor treatment.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas , Células Supresoras de Origen Mieloide , Animales , Ratones , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Humanos , Sistemas de Liberación de Medicamentos , Ratones Endogámicos C57BL , Línea Celular TumoralRESUMEN
BACKGROUND: Anti-PD-1-based immunotherapy has limited benefits in patients with pancreatic cancer. Accumulating data indicate that natural products exert antitumor activity by remodeling the tumor immune microenvironment. It has been reported that neogambogic acid (NGA), an active natural monomer extracted from Garcinia, has anti-inflammatory and antitumor effects. Nevertheless, there are few systematic studies on the antitumor efficacy and immunomodulatory effects of NGA in pancreatic cancer. METHODS: An orthotopic mouse model of pancreatic cancer was established and were treated with different doses of NGA. Tumor growth and ascites were observed. Flow cytometry and immunohistochemistry (IHC) were used to investigate the tumor immune microenvironment. CD11b+ MDSCs were infused back into mice with pancreatic cancer to observe tumor progression after NGA treatment. Bone marrow cells were induced to differentiate into MDSCs, and the effects of NGA on MDSCs were analyzed and the underlying mechanism was explored. The effects of NGA combined with an anti-PD-1 antibody on pancreatic cancer were further tested. RESULTS: NGA significantly inhibited the tumor growth and improve ascites character in pancreatic cancer model mice. Flow cytometry and IHC analysis revealed that NGA decreased the MDSCs proportion and infiltration in the tumor microenvironment. Moreover, adoptive MDSCs largely attenuated the inhibitory effect of NGA on the progression of pancreatic cancer. In addition, we showed that NGA significantly promoted apoptosis and inhibited the differentiation, migration and immunosuppressive function of MDSCs and decreased level of STAT3 and p-STAT3. Furthermore, we demonstrated that NGA synergistically enhanced the efficacy of anti-PD-1 antibodies against pancreatic cancer. CONCLUSION: NGA inhibited the progression of pancreatic cancer by inhibiting MDSCs in the tumor microenvironment, and enhanced the efficacy of anti-PD-1 therapy in the treatment of pancreatic cancer.
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Inhibidores de Puntos de Control Inmunológico , Células Supresoras de Origen Mieloide , Neoplasias Pancreáticas , Receptor de Muerte Celular Programada 1 , Microambiente Tumoral , Animales , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Ratones , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Línea Celular Tumoral , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Humanos , Ratones Endogámicos C57BL , Inmunoterapia/métodos , Factor de Transcripción STAT3/metabolismoRESUMEN
Metformin, a medication known for its anti-glycemic properties, also demonstrates potent immune system activation. In our study, using a 4T1 breast cancer model in BALB/C WT mice, we examined metformin's impact on the functional phenotype of multiple immune cells, with a specific emphasis on natural killer T (NKT) cells due to their understudied role in this context. Metformin administration delayed the appearance and growth of carcinoma. Furthermore, metformin increased the percentage of IFN-γ+ NKT cells, and enhanced CD107a expression, as measured by MFI, while decreasing PD-1+, FoxP3+, and IL-10+ NKT cells in spleens of metformin-treated mice. In primary tumors, metformin increased the percentage of NKp46+ NKT cells and increased FasL expression, while lowering the percentages of FoxP3+, PD-1+, and IL-10-producing NKT cells and KLRG1 expression. Activation markers increased, and immunosuppressive markers declined in T cells from both the spleen and tumors. Furthermore, metformin decreased IL-10+ and FoxP3+ Tregs, along with Gr-1+ myeloid-derived suppressor cells (MDSCs) in spleens, and in tumor tissue, it decreased IL-10+ and FoxP3+ Tregs, Gr-1+, NF-κB+, and iNOS+ MDSCs, and iNOS+ dendritic cells (DCs), while increasing the DCs quantity. Additionally, increased expression levels of MIP1a, STAT4, and NFAT in splenocytes were found. These comprehensive findings illustrate metformin's broad immunomodulatory impact across a variety of immune cells, including stimulating NKT cells and T cells, while inhibiting Tregs and MDSCs. This dynamic modulation may potentiate its use in cancer immunotherapy, highlighting its potential to modulate the tumor microenvironment across a spectrum of immune cell types.
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Neoplasias de la Mama , Metformina , Ratones Endogámicos BALB C , Metformina/farmacología , Metformina/uso terapéutico , Animales , Femenino , Ratones , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/efectos de los fármacos , Células T Asesinas Naturales/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Agentes Inmunomoduladores/farmacologíaRESUMEN
TPO receptor agonists (TPO-RAs) are a class of clinical second-line regimens for the treatment of primary immune thrombocytopenia (ITP). It can promote megakaryocyte maturation and increase platelet production, but its effect on immunosuppressive cells in patients with ITP has not been explored. Sixty-two ITP patients and 34 healthy controls (HCs) were included in this study. The proportion and functions of myeloid-derived immunosuppressive cells (MDSCs) in ITP patients and HCs were investigated. We found that the proportion and function of MDSCs in ITP patients treated with TPO-RAs were significantly higher than those treated with glucocorticoids (GCs), which was correlated with the clinical efficacy. The proportion and function of cytotoxic Th1 cells and CD8+T cells decreased, while the proportion and immunosuppressive function of Treg cells increased in ITP patients treated with TPO-RAs. We further proved, through MDSC depletion tests, that the inhibitory effect of MDSCs on Th1 cells and the promotion of Treg cells in the original immune micro-environment of GCs-treated ITP patients were impaired; however, these MDSCs' functions were improved in TPO-RAs-treated patients. Finally, we found that the KLF9 gene in MDSCs cells of ITP patients treated with TPO-RAs was down-regulated, which contribute to the higher mRNA expression of GADD34 gene and improved function of MDSCs. These results demonstrate a novel mechanism of TPO-RAs for the treatment of ITP through the assessment of MDSCs and their subsequent impact on T cells, which provides a new basis for TPO-RAs as first-line treatment approach to the treatment of ITP.
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Células Supresoras de Origen Mieloide , Púrpura Trombocitopénica Idiopática , Receptores de Trombopoyetina , Humanos , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/inmunología , Femenino , Masculino , Receptores de Trombopoyetina/agonistas , Adulto , Persona de Mediana Edad , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Anciano , Adulto Joven , Células TH1/inmunología , Células TH1/efectos de los fármacos , Inmunomodulación/efectos de los fármacos , Trombopoyetina/uso terapéutico , Trombopoyetina/farmacologíaRESUMEN
The immune system plays a pivotal role in combating diseases, including cancer, with monocytes emerging as key regulators of immune response dynamics. This article describes a novel strategy for cancer treatment centered on depleting myeloid-derived suppressor cells (MDSCs), to enhance the overall immune response while simultaneously targeting cancer cells directly. Alpha-fetoprotein (AFP) is an oncofetal protein that plays an important role in delivering nutrients to immature monocytes, embryonic, and cancer cells in a targeted manner. AFP can be repurposed, making it a vehicle for delivering toxins, rather than nutrients to kill cancer cells and deplete MDSCs in the tumor microenvironment (TME). Depleting monocytes not only stimulates the immune system but also improves the lymphocyte-to-monocyte ratio (LMR), often low in cancer patients. AFP combined with cytotoxic drugs, offers dual benefit-immune stimulation and targeted chemotherapy. Studies in xenograft models demonstrated high efficacy and safety of AFP-toxin conjugates, surpassing conventional targeted chemotherapy. Such conjugates have also been reported to provide superior efficacy and safety in cancer patients compared to chemotherapy. This approach, using AFP conjugated with toxins, either covalently or non-covalently, presents a safe and highly effective option for cancer immuno/chemotherapy.
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Inmunoterapia , Células Supresoras de Origen Mieloide , Neoplasias , alfa-Fetoproteínas , Humanos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/efectos de los fármacos , alfa-Fetoproteínas/metabolismo , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Inmunoterapia/métodos , Animales , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacosRESUMEN
Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy.
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Desoxicitidina , Gemcitabina , Inmunoterapia , Ratones Endogámicos BALB C , Células Supresoras de Origen Mieloide , Nanopartículas , Animales , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Células Supresoras de Origen Mieloide/efectos de los fármacos , Ratones , Inmunoterapia/métodos , Femenino , Nanopartículas/química , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Proliferación Celular/efectos de los fármacosRESUMEN
Myeloid-derived suppressor cells (MDSCs) are recognized as major immune suppressor cells in the tumor microenvironment that may inhibit immune checkpoint blockade (ICB) therapy. Here, we developed a Stattic-loaded mesoporous silica nanoparticle (PEG-MSN-Stattic) delivery system to tumor sites to reduce the number of MDSCs in tumors. This approach is able to significantly deplete intratumoral MSDCs and thereby increase the infiltration of T lymphocytes in tumors to enhance ICB therapy. Our approach may provide a drug delivery strategy for regulating the tumor microenvironment and enhancing cancer immunotherapy efficacy.
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Inmunoterapia , Células Supresoras de Origen Mieloide , Nanopartículas , Dióxido de Silicio , Microambiente Tumoral , Dióxido de Silicio/química , Nanopartículas/química , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Inmunoterapia/métodos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Animales , Ratones , Porosidad , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Polietilenglicoles/químicaRESUMEN
BACKGROUND: Currently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to investigate the anti-angiogenic and anti-inflammatory effects of cannabidiol and its mechanism of action. METHOD: An in vivo corneal neovascularization (CNV) model was established using the suture method to investigate the inhibitory effects of CBD on suture-induced corneal inflammation, pathological blood vessel formation, and lymphangiogenesis. Additionally, the impact of CBD on immune cells was studied. In vitro methodologies, including cell sorting and co-culture, were employed to elucidate its mechanism of action. RESULTS: Compared with the CNV group, CBD can inhibit CNV, lymphangiogenesis, and inflammation induced via the suture method. In addition, CBD specifically induced CD45+CD11b+Gr-1+ cell upregulation, which significantly inhibited the proliferation of CD4+ T lymphocytes in vitro and exhibited a CD31+ phenotype, proving that they were myeloid-derived suppressor cells (MDSCs). We administered anti-Gr-1 to mice to eliminate MDSCs in vivo and found that anti-Gr-1 partially reversed the anti-inflammatory and angiogenic effects of CBD. Furthermore, we found that compared with MDSCs in the normal group, CBD-induced MDSCs overexpress peroxisome proliferator-activated receptor-gamma (PPAR-γ). Administering PPAR-γ inhibitor in mice almost reversed the induction of MDSCs by CBD, demonstrating the role of PPAR-γ in the function of CBD. CONCLUSION: This study indicates that CBD may induce MDSCs upregulation by activating the nuclear receptor PPAR-γ, exerting anti-inflammatory, antiangiogenic, and lymphangiogenic effects, and revealing potential therapeutic targets for corneal neovascularization and lymphangiogenesis.
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Antiinflamatorios , Cannabidiol , Neovascularización de la Córnea , Linfangiogénesis , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide , Animales , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Neovascularización de la Córnea/tratamiento farmacológico , Neovascularización de la Córnea/patología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Ratones , Linfangiogénesis/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Modelos Animales de Enfermedad , Suturas , PPAR gamma/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Masculino , Córnea/patología , Córnea/efectos de los fármacos , Células CultivadasRESUMEN
Myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting melanoma metastasis. Reprogramming MDSCs into mature M1 macrophages has emerged as a strategy to inhibit metastasis. Decitabine (Dec) is known to eradicate MDSCs and suppress tumor growth. In this study, we provide evidence that Dec not only reduces the MDSC population by inducing apoptosis, arresting cell cycle, and impairing recruitment, but also suppresses their immunosuppressive function by downregulating related genes and facilitating differentiation into M1 macrophages. Transcriptomic analysis of Dec-treated MDSCs revealed a marked downregulation of immunosuppressive genes including S100a9, S100a8, Vegf, Cxcr2, and Nos2. Meanwhile, M1 macrophage-associated genes involved in immune activation were upregulated, such as Ddx58, Isg15, Tap1, Ccl5, Cxcl9, and Cxcl10. Further bioinformatic analysis indicated that Dec promotes MDSC-to-M1 macrophage differentiation and activates innate immune pathways including NOD-like signaling to enhance anti-tumor immunity. Time-course studies implied that Dec upregulates myeloid transcription factor Irf7 to initiate MDSC differentiation and orchestrate the anti-tumor immune response. Collectively, our study unveils a novel dual-functional mechanism of Dec as both a cytotoxic agent reducing MDSCs and an inducer of their differentiation into M1 macrophages, thereby alleviating immunosuppression. This highlights Dec's potential for clinical melanoma metastasis suppression.
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Decitabina , Melanoma , Células Supresoras de Origen Mieloide , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Animales , Decitabina/farmacología , Ratones , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/inmunología , Humanos , Ratones Endogámicos C57BL , Diferenciación Celular/efectos de los fármacos , Antimetabolitos Antineoplásicos/farmacología , Línea Celular Tumoral , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Apoptosis/efectos de los fármacos , Tolerancia Inmunológica/efectos de los fármacosRESUMEN
Inflammatory bowel disease (IBD) describes a group of clinically common autoimmune diseases characterized by chronic intestinal inflammation, with gender differences in prevalence. Estrogen has been previously shown to exert anti-inflammatory action in IBD development, however, the mechanisms remain obscure. Recent research has revealed that myeloid-derived suppressor cells (MDSCs) play a protective role in IBD pathogenesis. To investigate the molecular mechanisms of estrogen steroid 17ß-estradiol (E2) in IBD progression, we established IBD mouse models (DNB-induced) with or without prior ovariectomy (OVX) and E2 implantation. We found that OVX led to worse IBD symptoms and reduced MDSCs frequency, whereas E2 significantly alleviated these effects in vivo. Moreover, in vitro experiments showed that E2 promoted the proliferation and immunosuppressive function of MDSCs through phosphorylation of Stat3 and p65. Mechanistically, E2-mediated Stat3/p65 phosphorylation depends on the interaction between HOTAIR, a long non-coding RNA that are well-known in MDSCs proliferation, and Stat3/p65 respectively. In conclusion, our study revealed that E2 promotes the expansion and immunosuppressive function of MDSCs, and thus diminished the occurrence and development of IBD.
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Estradiol , Enfermedades Inflamatorias del Intestino , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Factor de Transcripción STAT3/metabolismo , Estradiol/farmacología , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Ratones , Femenino , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Proliferación Celular/efectos de los fármacos , Estrógenos/metabolismo , Estrógenos/farmacología , Fosforilación/efectos de los fármacos , Ovariectomía , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease that affects the quality of life and mental health of approximately 150 million people worldwide. Ze-Qi-Tang (ZQT) is a classic compound used in China for lung disease; however, its mechanism of action in psoriasis remains unclear. This study aimed to investigate the therapeutic effect of the ZQT formula on psoriasis and explore the underlying molecular mechanisms. METHODS: Peripheral blood samples were collected from patients with psoriasis and healthy individuals. Flow cytometry was used to detect changes in the proportions of myeloid-derived suppressor cells (MDSCs) and other immune cells. Psoriasis was induced in mice by the daily application of imiquimod. ZQT was administered separately or in combination with anti-Gr1 antibody to deplete MDSC. The glycolysis levels of the MDSCs were detected using a Seahorse analyzer. The p21/Hif1α/Glut1 pathway was identified and validated by mRNA sequence, RT-qPCR, WB, IF, and the application of p21 inhibitor UC2288. RESULTS: The number of MDSCs was significantly increased in patients with psoriasis, with the increased expression of p21, Hif1α, and Glut1 in MDSCs. ZQT significantly alleviated psoriasis-like skin lesions in mice. ZQT formula significantly reduced the number of MDSCs in psoriatic-like mice and enhanced their suppressive capacity for T cells. The efficacy of ZQT in alleviating psoriatic dermatitis is compromised by MDSC depletion. ZQT decreased the expressions of p21, Hif1α, and Glut1-induced glycolysis in MDSCs, thereby inhibiting Th17 cell differentiation. CONCLUSION: These suggest that ZQT alleviates IMQ-induced psoriatic dermatitis, by inhibiting p21/Hif1α/Glut1-induced glycolysis in MDSCs.
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Regulación hacia Abajo , Medicamentos Herbarios Chinos , Transportador de Glucosa de Tipo 1 , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Células Supresoras de Origen Mieloide , Psoriasis , Animales , Psoriasis/tratamiento farmacológico , Transportador de Glucosa de Tipo 1/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Glucólisis/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Humanos , Ratones , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/metabolismo , Masculino , Regulación hacia Abajo/efectos de los fármacos , Femenino , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Adulto , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos BALB C , Imiquimod , Persona de Mediana EdadRESUMEN
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) negatively modulate immune activity. Prior investigations have shown much promise in using MDSCs-assisted immunotherapy for organ transplantation patients. Additionally, owing to its immunosuppressive activity, MDSCs can also be used to manage immune-associated disorders. METHODS: Granulocyte-macrophage colony-stimulating factor (GM-CSF) was employed to stimulate myeloid progenitor cell differentiation. Triptolide (PG490) was introduced toward the later phases of in vitro MDSCs induction. Lastly, real-time PCR (RT-PCR) and flow cytometry were used to assess transcript expression and cell phenotype, and a mouse skin transplantation model was established to evaluate the MDSCs-mediated immune suppression in vivo. RESULTS: Co-stimulation with PG490 and GM-CSF potently induced myeloid-derived monocytes to form MDSCs, with remarkable immune-suppressive activity. The underlying mechanism involved downregulation of T cell proliferation, activation, enhancement of inflammatory cytokine release, as well as T cell conversion to Treg cells. PG490 strongly enhanced iNOS expression in MDSCs, and iNOS inhibition successfully reversed the immune-suppression. The PG490- and GM-CSF-induced MDSCs substantially extended survival duration of murine skin grafts, thereby validating their strong immune-suppressive activity in vivo. CONCLUSIONS: Herein, we presented a new approach involving MDSCs-based immunosuppression in vitro. PG490 and GM-CSF co-treatment strongly induced immuno-suppressive activity in MDSCs both in vitro and in vivo. Our findings highlight the promise of applying MDSCs-based therapy in clinical organ transplantation treatment.
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Diferenciación Celular , Diterpenos , Compuestos Epoxi , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Monocitos , Células Supresoras de Origen Mieloide , Fenantrenos , Diterpenos/farmacología , Fenantrenos/farmacología , Compuestos Epoxi/farmacología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/metabolismo , Animales , Humanos , Monocitos/inmunología , Monocitos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Ratones , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Trasplante de Piel/métodos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Inmunosupresores/farmacología , Ratones Endogámicos C57BL , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Terapia de Inmunosupresión/métodos , Células CultivadasRESUMEN
We previously demonstrated that the C-E-cad protein encoded by circ-E-cadherin promotes the self-renewal of glioma stem cells. The expression pattern of C-E-cad in breast cancer and its potential function in the tumor microenvironment are unclear. The expression of circ-E-cadherin and C-E-cad was detected in breast cancer specimens. The influence of C-E-cad expression on MDSCs was assessed using FACS and in vivo tumorigenesis experiments. The synergistic effect of anti-C-E-cad and anti-PD-1 antibodies was validated in vivo. circ-E-cadherin and the encoded protein C-E-cad were found to be upregulated in breast cancer vs. normal samples. C-E-cad promotes the recruitment of MDSCs, especially PMN-MDSCs. C-E-cad activates EGFR signaling in tumor cells and promotes the transcription of CXCL8; moreover, C-E-cad binds to MDSCs and maintains glycolysis in PMN-MDSCs. Targeting C-E-cad enhanced anti-PD-1 efficiency. Our data suggested that C-E-cad is markedly overexpressed in breast cancer and promotes MDSC recruitment and survival. Targeting C-E-cad increases the efficacy of immune checkpoint inhibitor therapy.
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Neoplasias de la Mama , Cadherinas , Células Supresoras de Origen Mieloide , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Humanos , Femenino , Cadherinas/metabolismo , Cadherinas/genética , Animales , Microambiente Tumoral/efectos de los fármacos , Línea Celular Tumoral , Ratones Endogámicos BALB C , Ratones , Receptores ErbB/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/genética , Antígenos CD/metabolismo , Antígenos CD/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
Epigenetic drugs (epi-drugs) can destruct cancer cells and initiate both innate and adaptive immunity, yet they have achieved very limited success in solid tumors so far, partly attributing to their concurrent induction of the myeloid-derived suppressor cell (MDSC) population. Here, dissociable Siamese nanoparticles (SIANPs) are developed for tumor cell-targeted delivery of epi-drug CM-272 and MDSC-targeted delivery of small molecule inhibitor Ibrutinib. The SIANPs are assembled via interparticle DNA annealing and detached via tumor microenvironment-triggered strand separation. Such binary regulation induces endogenous retrovirus expression and immunogenic cell death in tumor cells while restraining the immunosuppressive effects of MDSCs, and synergistically promotes dendritic cell maturation and CD8+ T cell activation for tumor inhibition. Significantly, immune microenvironment remodeling via SIANPs further overcomes tumor resistance to immune checkpoint blockade therapy. This study represents a two-pronged approach for orchestrating immune responses, and paves a new way for employing epi-drugs in cancer immunotherapy.