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Despite its success in achieving the long-term survival of 10-30% of treated individuals, immune therapy is still ineffective for most patients with cancer1,2. Many efforts are therefore underway to identify new approaches that enhance such immune 'checkpoint' therapy3-5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9-a key protein in the regulation of cholesterol metabolism6-8-can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9's cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9-either through genetic deletion or using PCSK9 antibodies-increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer.
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Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Inhibidores de PCSK9 , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Lisosomas/metabolismo , Ratones , Neoplasias/metabolismo , Neoplasias/patología , Proproteína Convertasa 9/deficiencia , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/inmunología , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Splenectomy may lead to severe postoperative complications, including sepsis and cancers. A possible solution to this problem is heterotopic autotransplantation of the spleen. Splenic autografts rapidly restore the regular splenic microanatomy in model animals. However, the functional competence of such regenerated autografts in terms of lympho- and hematopoietic capacity remains uncertain. Therefore, this study aimed to monitor the dynamics of B and T lymphocyte populations, the monocyte-macrophage system, and megakaryocytopoiesis in murine splenic autografts. METHODS: The model of subcutaneous splenic engraftment was implemented in C57Bl male mice. Cell sources of functional recovery were studied using heterotopic transplantations from B10-GFP donors to C57Bl recipients. The cellular composition dynamics were studied by immunohistochemistry and flow cytometry. Expression of regulatory genes at mRNA and protein levels was assessed by real-time PCR and Western blot, respectively. RESULTS: Characteristic splenic architecture is restored within 30 days post-transplantation, consistent with other studies. The monocyte-macrophage system, megakaryocytes, and B lymphocytes show the highest rates, whereas the functional recovery of T cells takes longer. Cross-strain splenic engraftments using B10-GFP donors indicate the recipient-derived cell sources of the recovery. Transplantations of scaffolds populated with splenic stromal cells or without them afforded no restoration of the characteristic splenic architecture. CONCLUSIONS: Allogeneic subcutaneous transplantation of splenic fragments in a mouse model leads to their structural recovery within 30 days, with full reconstitution of the monocyte-macrophage, megakaryocyte and B lymphocyte populations. The circulating hematopoietic cells provide the likely source for the cell composition recovery.
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Bazo , Esplenectomía , Masculino , Ratones , Animales , Bazo/fisiología , Bazo/trasplante , Trasplante Autólogo , Linfocitos T , Modelos Animales de EnfermedadRESUMEN
Few studies have focused on the influence of environmental conditions on the bioavailability of pollutants interacted with nanomaterials in organisms. In this study, we primarily compared the influence of multiwalled carbon nanotubes (MWCNTs) on the bioavailability of fluoxetine in zebrafish (Danio rerio) larva under different environmental conditions: natural organic matter (NOM) and salinity. The results showed that fluoxetine accumulated in the larvae and then transformed into the metabolite norfluoxetine, with the metabolic rates from 2.8 to 3.5. Following co-exposure to MWCNTs, the accumulation of fluoxetine and norfluoxetine were further enhanced, suggesting a superior carrier of MWCNTs for fluoxetine, especially the functional MWCNTs. The consistent increase in the fluoxetine and norfluoxetine accumulation highlights the bioavailability of absorbed fluoxetine on MWCNTs in zebrafish larvae. The presence of NOM promoted the accumulation of fluoxetine and norfluoxetine in zebrafish, but alleviated the carrier effects of MWCNTs, acting as a natural antidote. Salinity negatively influenced the bioavailability of fluoxetine in the larvae, and further reversed the enhancements caused by MWCNTs. These findings provide a new insight into the influence of environmental conditions on the interactions between nanomaterials and pollutants in organisms.
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Fluoxetina/farmacocinética , Larva/metabolismo , Nanotubos de Carbono , Contaminantes Químicos del Agua/farmacocinética , Pez Cebra/metabolismo , Animales , Fluoxetina/análogos & derivados , Fluoxetina/metabolismoRESUMEN
D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 µg (the acute cohort) and 0, 0.05, 0.1, 0.35 µg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 µg (5/10 rats) and 0.35 µg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 µg, and the no-observed-adverse-effect-level was 0.05 µg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.
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Convección , Sistemas de Liberación de Medicamentos , Evaluación Preclínica de Medicamentos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/toxicidad , Inmunotoxinas/administración & dosificación , Inmunotoxinas/toxicidad , Anticuerpos de Cadena Única/administración & dosificación , Anticuerpos de Cadena Única/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Femenino , Concentración 50 Inhibidora , Inyecciones Intraventriculares , Masculino , Ratas Sprague-DawleyRESUMEN
Activation of a thrombin receptor, protease-activated receptor-1 (PAR-1), induces angiogenesis, cell proliferation, and invasion in tumors. The present study examined the effect of host PAR-1 gene deletion on glioma growth in a mouse model. F98 glioma cells were implanted into the right caudate of either wild type (WT) or PAR-1 knockout (KO) mice. Mice underwent magnetic resonance imaging (MRI) and the brains were used for measurements of brain water content and tumor mass. Levels of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) were also measured by ELISA (enzyme-linked immunosorbent assay). We found brain water content in the ipsilateral hemisphere and the tumor mass were significantly lower in PAR-1 KO than WT mice at day 12 after implantation of F98 cells (p < 0.05). HIF-1α protein levels in the ipsilateral hemisphere were higher in the WT mice (373 ± 25 pg/g brain tissue vs 333 ± 35 pg/g brain tissue in PAR-1 KO mice, p < 0.05) 7 days after F98 cell implantation. VEGF protein levels were also higher in the ipsilateral hemisphere of WT mice (219 ± 21 vs 166 ± 22 pg/g brain tissue in PAR-1 KO mice, p < 0.01). In conclusion, PAR-1 has a role in glioma growth and could be a new therapeutic target for gliomas.
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Neoplasias Encefálicas/genética , Glioma/genética , Receptor PAR-1/genética , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Glioma/metabolismo , Glioma/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Imagen por Resonancia Magnética , Ratones , Ratones Noqueados , Trasplante de Neoplasias , Ratas , Carga Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
von Hippel-Lindau (VHL), known as a tumor suppressor gene, is frequently mutated in clear cell renal cell carcinoma (ccRCC). However, VHL mutation is not sufficient to promote tumor formation. In most cases other than ccRCC, VHL loss alters cellular homeostasis and causes cell stress and metabolic changes by stabilizing hypoxia-inducible factor (HIF) levels, resulting in a fitness disadvantage. In addition, the function of VHL in regulating immune response is still not well established. In this study, we demonstrate that VHL loss enhances the efficacy of anti-programmed death 1 (PD1) treatment in multiple murine tumor models in a T cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1α/2α induced by VHL loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA, which triggered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation and induced type I interferons. Our study thus provided mechanistic insights into the role of VHL gene loss in boosting antitumor immunity.
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To investigate the influences of functional groups on the biological effects caused by microplastics, the accumulation of three polystyrene microplastics (PS, PS-NH2, and PS-COOH) in zebrafish (Danio rerio) embryos were analyzed, and then the responses of metabolic functions and microbial communities in zebrafish larvae were revealed using the combination of the microbiome and metabolome methods. The results showed that all microplastics could accumulate in zebrafish with concentrations ranging from 143 to 175 µg·g-1, and there were no significant differences in the accumulation potentials among different PS treatments. Exposure to plain PS significantly affected the metabolic capacity of aminoglycosides in zebrafish larvae, whereas the metabolic processes of amino acids were affected by PS-NH2. In the PS-COOH treatment, the metabolic pathways of the tricarboxylic acid cycle, amino acids, and glycolysis in zebrafish were markedly altered. The metabolic functions of zebrafish larvae were changed by all PS microplastics, resulting in toxic effects on zebrafish, and the functional group modification of microplastics may have further enhanced these toxicities. Compared to that in the control, exposure to PS-NH2 significantly reduced the diversity of microbial communities in zebrafish larvae and increased the proportion of Proteobacteria in the composition, leading to an imbalance of the bacterial community in zebrafish and thus disrupting the metabolic functions in the fish. Therefore, the functional modifications of microplastics may significantly alter the related stresses on aquatic organisms, leading to unpredictable ecological risks.
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Microplásticos , Contaminantes Químicos del Agua , Animales , Pez Cebra/metabolismo , Plásticos , Contaminantes Químicos del Agua/metabolismo , Poliestirenos , Larva/metabolismo , AminoácidosRESUMEN
Background: Hypertrophic cardiomyopathy (HCM), identified as a primary cause of sudden cardiac death (SCD), intertwines with pulmonary hypertension (PH) to amplify cardiovascular morbidity. This complex synergy poses significant therapeutic challenges due to the absence of drugs specifically targeting their concurrent manifestation. This study seeks to unravel the molecular intricacies linking HCM and PH, aiming to lay the groundwork for targeted therapeutic interventions. Methods: Through the analysis of gene expression profiles from datasets GSE36961 (HCM) and GSE113439 (PH) within the public data repository of Gene Expression Omnibus (GEO), this research systematically identified differentially expressed genes (DEGs), conducted extensive functional annotations, and constructed detailed protein-protein interaction (PPI) networks to uncover crucial hub genes. Further, co-expression analyses, alongside drug prediction and molecular docking simulations, were employed to pinpoint potential therapeutic agents that could ameliorate the combined pathology of HCM and PH. Results: Our comprehensive analysis unearthed 79 DEGs shared between HCM and PH, highlighting fourteen as pivotal hub genes. Validation across three additional datasets (GSE35229, GSE32453, and GSE53408) from GEO accentuated secreted phosphoprotein 1 (SPP1) as a key gene of interest. Remarkably, the study identified tacrolimus, ponatinib, bosutinib, dasatinib, doxorubicin, and zanubrutinib as promising drugs for addressing the dual challenge of HCM and PH. Conclusions: The findings of this investigation shed light on the genetic underpinnings of HCM and PH's simultaneous occurrence, emphasizing the central role of SPP1 in their pathogenesis. The identification of six candidate drugs offers a hopeful vista for future therapeutic strategies targeting this complex cardiovascular interplay, marking a significant stride towards mitigating the compounded morbidity of HCM and PH. Future mechanistic and clinical studies are warranted for the investigation of this potential target and therapeutics.
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Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-o-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson's disease, in glioma treatment. Analysis of TCGA data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in glioma patients.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.
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Enfermedades Cardiovasculares , Hipercolesterolemia , Humanos , Proproteína Convertasa 9/genética , Anticuerpos Monoclonales/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , SubtilisinasRESUMEN
Our study demonstrates the glioma tumor antigen podoplanin to be present at very high levels (>90%) in both glioblastoma (D2159MG, D08-0308MG and D08-0493MG) and medulloblastoma (D283MED, D425MED and DAOY) xenografts and cell line. We constructed a novel recombinant single-chain antibody variable region fragment (scFv), NZ-1, specific for podoplanin from the NZ-1 hybridoma. NZ-1-scFv was then fused to Pseudomonas exotoxin A, carrying a C-terminal KDEL peptide (NZ-1-PE38KDEL). The immunotoxin (IT) was further stabilized by a disulfide (ds) bond between the heavy-chain and light-chain variable regions as the construct NZ-1-(scdsFv)-PE38KDEL. NZ-1-(scdsFv)-PE38KDEL exhibited significant reactivity to glioblastoma and medulloblastoma cells. The affinity of NZ-1-(scdsFv), NZ-1-(scdsFv)-PE38KDEL and NZ-1 antibody for podoplanin peptide was 2.1 × 10(-8) M, 8.0 × 10(-8) M and 3.9 × 10(-10) M, respectively. In a protein stability assay, NZ-1-(scdsFv)-PE38KDEL retained 33-98% of its activity, whereas that of NZ-1-PE38KDEL declined to 13% of its initial levels after incubation at 37°C for 3 days. In vitro cytotoxicity of the NZ-1-(scdsFv)-PE38KDEL was measured in cells isolated from glioblastoma xenografts, D2159MG, D08-0308MG and D08-0493MG, and in the medulloblastoma D283MED, D425MED and DOAY xenografts and cell line. The NZ-1-(scdsFv)-PE38KDEL IT was highly cytotoxic, with an 50% inhibitory concentration in the range of 1.6-29 ng/ml. Significantly, NZ-1-(scdsFv)-PE38KDEL demonstrated tumor growth delay, averaging 24 days (p < 0.001) and 21 days (p < 0.001) in D2159MG and D283MED in vivo tumor models, respectively. Crucially, in the D425MED intracranial tumor model, NZ-1-(scdsFv)-PE38KDEL caused a 41% increase in survival (p ≤ 0.001). In preclinical studies, NZ-1-(scdsFv)-PE38KDEL exhibited significant potential as a targeting agent for malignant brain tumors.
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ADP Ribosa Transferasas/inmunología , Toxinas Bacterianas/inmunología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Exotoxinas/inmunología , Glioblastoma/tratamiento farmacológico , Glioblastoma/inmunología , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/inmunología , Glicoproteínas de Membrana/inmunología , Anticuerpos de Cadena Única/inmunología , Factores de Virulencia/inmunología , ADP Ribosa Transferasas/uso terapéutico , Toxinas Bacterianas/uso terapéutico , Línea Celular Tumoral , Exotoxinas/uso terapéutico , Femenino , Humanos , Masculino , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéutico , Factores de Virulencia/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Exotoxina A de Pseudomonas aeruginosaRESUMEN
Organic ultraviolet filters (OUVFs) are new hydrophobic organic pollutants in the aquatic environment. When ingested by aquatic organisms, OUVFs can induce a variety of toxic effects in organisms and be transferred to offspring. However, as the main active ingredient in sunscreens, OUVFs have rarely been investigated for their melanin interference toxicity or transgenerational toxic effects on aquatic organisms and their interactive toxic effects with nanoplastics (NPs). Here, we show the mechanism by which OUVFs interfere with melanogenesis in parental or offspring zebrafish and the effect of polystyrene (PS) NPs on the melanin-interference effect of OUVFs. We found that EHS induced significant enrichment of the melanogenesis pathway, inhibited the expression of the key melanin gene microphthalmia-associated transcription factor a (mitfa) and induced the mitf tyrosinase (tyr)-dopachrome tautomerase (dct)-tyrosinase related protein 1 (tyrp1) signaling cascade in parents, which ultimately induced a decrease in melanin content. After reproduction, transgenerational melanin interference effects of EHS may occur through the maternal inheritance of mitfa. Coexisting PS-NPs may inhibit the melanin interference toxicity or transgenerational toxicity of EHS by reducing ultraviolet irritation to the skin through adsorption of EHS. Our results demonstrate the ecotoxic potential of OUVFs in terms of melanin interference and the interference of PS-NP carrier effects on the toxicity of OUVFs. We anticipate that our assay will contribute to the assessment of the toxic effects of OUVFs and provide a basis for the interactive ecotoxicity assessment of PS-NPs and hydrophobic organic pollutants.
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Melaninas , Contaminantes Químicos del Agua , Animales , Melaninas/metabolismo , Monofenol Monooxigenasa/genética , Poliestirenos/toxicidad , Poliestirenos/metabolismo , Microplásticos/metabolismo , Metilación de ADN , Pez Cebra/genética , Pez Cebra/metabolismo , Contaminantes Químicos del Agua/toxicidad , Salicilatos/toxicidadRESUMEN
Targeted therapy and immunotherapy have brought hopes for precision cancer treatment. However, complex physiological barriers and tumor immunosuppression result in poor efficacy, side effects, and resistance to antitumor therapies. Bacteria-mediated antitumor therapy provides new options to address these challenges. Thanks to their special characteristics, bacteria have excellent ability to destroy tumor cells from the inside and induce innate and adaptive antitumor immune responses. Furthermore, bacterial components, including bacterial vesicles, spores, toxins, metabolites, and other active substances, similarly inherit their unique targeting properties and antitumor capabilities. Bacteria and their accessory products can even be reprogrammed to produce and deliver antitumor agents according to clinical needs. This review first discusses the role of different bacteria in the development of tumorigenesis and the latest advances in bacteria-based delivery platforms and the existing obstacles for application. Moreover, the prospect and challenges of clinical transformation of engineered bacteria are also summarized.
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Antineoplásicos , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Inmunoterapia/métodos , BacteriasRESUMEN
Despite a moderate mutation burden, clear cell renal cell carcinoma (ccRCC) responds well to immune checkpoint blockade (ICB) therapy. Here we report that loss-of-function mutations in the von Hippel-Lindau (VHL) gene, the most frequent in ccRCC, underlies its responsiveness to ICB therapy. We demonstrate that genetic knockout of the VHL gene enhanced the efficacy of anti-PD-1 therapy in multiple murine tumor models in a T cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1α and HIF2α induced by VHL gene loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA (mtDNA), which triggered cGAS-STING activation and induced type I interferons. Our study thus provided novel mechanistic insights into the role of VHL gene loss in potentiating ccRCC immunotherapy.
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AIM: To provide a profile of second malignant neoplasms (SMN) in patients with childhood primary malignant brain tumour originating from neuroepithelial tissues with latest data in a population-based study. METHODS: Surveillance, Epidemiology, and End Results (SEER) database (1973-2007) was used to identify above-stated patients. SMN patients were further identified, and standardised incidence ratios (SIRs) and excess absolute risks (EARs) for risk-factor-decided subgroups were calculated. Univariate and multivariate analyses of the association between cumulative incidence of SMN and the risk factors were performed in the whole population. RESULTS: A total of 106 patients were identified as having SMNs. EARs peaked at age at primary diagnosis of 10-14. Males had higher SIRs and EARs than females. Both SIRs and EARs increased after 1990. Age was statistically significant in both univariable and multivariable analyses for cumulative incidence of SMN and RT was not significant in both the analyses, in the whole population of 9075 patients. After follow-up recalculation, matched patients in the ≥1990 group had slightly shorter median interval between primary and secondary cancer than those in the <1990 group, but with no significance. CONCLUSION: The risk of SMN in children with primary malignant brain tumours in a more advanced treatment era might have changed. During making further advances in the treatment of these neoplasms, minimising toxicities while maintaining promising prognostic outcomes will keep being our goal.
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Neoplasias Encefálicas , Neoplasias Primarias Secundarias/epidemiología , Vigilancia de la Población/métodos , Adolescente , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Masculino , Medición de Riesgo , Factores Sexuales , Factores de Tiempo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Emerging evidence has demonstrated that radiotherapy (RT) can not only cause direct damage to cancer cells but also lead to immunogenic cell death (ICD), which involves the activation of host antitumor immune response in tumor immune microenvironment (TIME). RT-induced ICD comprises the release of damage-associated molecular patterns (DAMPs) from dying cancer cells that result in the activation of tumor-specific immunity to elicit long-term antitumor efficacy in both original and abscopal tumor sites. Adenosine triphosphate (ATP), as an important DAMP released by irradiated cancer cells and an essential factor within purinergic pathway, can be further hydrolyzed to adenosine (ADO) by two key ectonucleotidases, CD39 and CD73, to further modulate the antitumor immunity in TIME through purinergic signaling via the interaction to its specific receptors such as adenosine 2A receptor (A2AR) and A2BR widely expressed on the surface of the components in TIME, including cancer cells and many immune effector cells. In this review, we first introduced key components in purinergic pathway including ATP, ADO, their receptors, and essential ectonucleotidases. Then we reviewed the regulation of ATP and ADO levels and their main mechanisms by which they promote tumor growth and broadly suppress antitumor immunity through inhibiting the pro-inflammatory response of dendritic cells, cytotoxic T lymphocytes, and natural killer cells, while improving the anti-inflammatory response of regulatory T cells, macrophages, and myeloid-derived suppressor cells in TIME, especially after irradiation. Finally, we presented an overview of dozens of promising therapeutics including pharmacological antagonists and specific antibodies targeting ADO receptors and ectonucleotidases CD39 or CD73 investigated in the clinic for cancer treatment, especially focusing on the preclinical studies and clinical trials being explored for blocking the purinergic signaling to enhance RT as a combination antitumor therapeutic strategy, which has a robust potential to be translated to the clinic in the future.
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Muerte Celular Inmunogénica , Neoplasias , Adenosina/metabolismo , Adenosina Trifosfato/metabolismo , Humanos , Neoplasias/metabolismo , Linfocitos T Reguladores/metabolismo , Microambiente TumoralRESUMEN
The type I interferon response plays a pivotal role in promoting antitumor immune activity in response to radiotherapy. The identification of approaches to boost the radiation-induced type I interferon response could help improve the efficacy of radiotherapy. Here we show that the histone methyltransferase SETDB1 is a potent suppressor of radiation-induced endogenous retrovirus expression. SETDB1 inhibition significantly enhanced the efficacy of radiotherapy by promoting radiation-induced viral mimicry to upregulate type I interferons. SETDB1 expression correlated with radiotherapy efficacy in human non-small cell carcinoma and melanoma patients. In a murine tumor model, genetic deletion of Setdb1 significantly enhanced radiotherapy efficacy, and Setdb1-deficient tumors had enhanced intratumoral lymphocyte infiltration, an observation confirmed in human cancer samples. Setdb1 deficiency led to increased basal and radiation-induced endogenous retrovirus (ERV) expression, enhanced MDA5/MAVS signaling, and upregulated type I interferons, which were essential for SETDB1 deficiency-induced radiosensitization. Taken together, these data suggest that inhibition of SETDB1 is a promising approach to enhance cancer radiotherapy efficacy by promoting radiation-induced viral mimicry and antitumor immunity through ERV induction. SIGNIFICANCE: The identification of the SETDB1-mediated suppression of radiotherapy-induced viral mimicry reveals SETDB1 inhibition as a potential approach to sensitize tumors to radiotherapy by enhancing the type I interferon response.
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Retrovirus Endógenos , N-Metiltransferasa de Histona-Lisina , Interferón Tipo I , Melanoma , Animales , Retrovirus Endógenos/genética , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Interferón Tipo I/inmunología , Melanoma/genética , Melanoma/inmunología , Melanoma/radioterapia , Ratones , Transducción de SeñalRESUMEN
Microplastics as the most challenging environmental pollutants in ocean have raised increasing concerns, however, the understanding of microplastics in freshwater falls far behind. The main objective of this study is to assess the microplastic pollution in an urbanized river affected by water diversion. The active biomonitoring method with caged native crucian carp (Carassius auratus) was used to evaluate the microplastic risk for riverine fish. It found that microplastic abundance in water and sediment was 1467-20567 items/m³ and 1115-6380 items/kg, respectively. The operational water diversion did not alleviate the microplastic pollution in water. The abundance in sediment was not simply proportional to that in water. However, the main morphological profiles and polymer composition were similar in the water and sediment. Microplastic accumulation in caged fish intestine was higher than that in gill. Intestine seems to be an ideal tissue to reflect the microplastic pollution in water. Shapes may contribute to the accumulation in fish. Based on the pollution load index, all caged fish did not reach to high level risks. These findings not only improve the understanding on the impact of water diversion on microplastic pollution in urban river, but also shed an insight in the related risk for riverine fish.
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Microplásticos , Contaminantes Químicos del Agua , Animales , Monitoreo Biológico , China , Monitoreo del Ambiente , Plásticos , Ríos , Agua , Contaminantes Químicos del Agua/análisisRESUMEN
Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia telangiectasia mutated (ATM) protein plays a central role in sensing DNA double-stranded breaks (DSBs) and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance ICB therapy. However, the molecular mechanism involved has not been clearly elucidated. Here, we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA (mtDNA) and activation of the cGAS/STING pathway. We show that genetic depletion of ATM in murine cancer cells delayed tumor growth in syngeneic mouse hosts in a T cell-dependent manner. Furthermore, chemical inhibition of ATM potentiated anti-PD-1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating mitochondrial transcription factor A (TFAM), which led to mtDNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits of ICB therapy. Our study therefore provides strong evidence that ATM may serve as both a therapeutic target and a biomarker to enable ICB therapy.
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ADN Mitocondrial , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia , Proteínas de la Membrana , Proteínas de Neoplasias , Neoplasias Experimentales , Nucleotidiltransferasas , Transducción de Señal , Animales , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/inmunología , Línea Celular Tumoral , Codón sin Sentido , ADN Mitocondrial/genética , ADN Mitocondrial/inmunología , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/terapia , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
Anaplastic oligodendroglioma (AO) is an uncommon intracranial tumor and prognosis is poor. In this study, we assessed the factors affecting the prognosis of AO patients. Seventy AO patients were recruited from 2001 to 2006 in Shanghai Huashan Hospital of Fudan University; all were treated surgically. Kaplan-Meier survival analysis and Cox regression analysis were used to analyze the prognostic effects of 14 different factors, which were selected from clinical, radiological, pathological, and treatment variables. The results showed that chemotherapy, age, primary or secondary tumors, preoperative Karnofsky Performance Scale (KPS) scores, the presence of epilepsy at initial presentation, radiological contrast infusion, and neurological parameters all correlated with the prognosis of the patients. Furthermore, Cox multivariate analysis also showed that the age (P < 0.048), primary or secondary tumors (P < 0.010), and chemotherapy (P < 0.010) were significantly correlated with the prognosis of the patients. Age and chemotherapy correlated with the prognosis of AO. The patients younger than 50 years old and who received regular chemotherapy were likely to achieve a good outcome. Moreover, individualized treatment after molecular biological typing of AO may improve the prognosis of AO.