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1.
J Clin Invest ; 133(12)2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37317970

RESUMO

While the rapid advancement of immunotherapies has revolutionized cancer treatment, only a small fraction of patients derive clinical benefit. Eradication of large, established tumors appears to depend on engaging and activating both innate and adaptive immune system components to mount a rigorous and comprehensive immune response. Identifying such agents is a high unmet medical need, because they are sparse in the therapeutic landscape of cancer treatment. Here, we report that IL-36 cytokine can engage both innate and adaptive immunity to remodel an immune-suppressive tumor microenvironment (TME) and mediate potent antitumor immune responses via signaling in host hematopoietic cells. Mechanistically, IL-36 signaling modulates neutrophils in a cell-intrinsic manner to greatly enhance not only their ability to directly kill tumor cells but also promote T and NK cell responses. Thus, while poor prognostic outcomes are typically associated with neutrophil enrichment in the TME, our results highlight the pleiotropic effects of IL-36 and its therapeutic potential to modify tumor-infiltrating neutrophils into potent effector cells and engage both the innate and adaptive immune system to achieve durable antitumor responses in solid tumors.


Assuntos
Imunidade Adaptativa , Neutrófilos , Humanos , Citocinas , Terapia de Imunossupressão , Imunoterapia
2.
Clin Cancer Res ; 19(21): 5952-9, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24056786

RESUMO

PURPOSE: Oncolytic viruses (OV) based on herpes simplex virus type 1 (HSV1) are being used in clinical trials for a variety of cancers. The OV, rQNestin34.5, uses a nestin promoter/enhancer to selectively drive robust viral replication in malignant glioma cells. We have discovered that this promoter becomes extensively methylated in infected glioma cells, reducing OV efficacy. EXPERIMENTAL DESIGN: We used demethylating drugs [5-azacytidine (5-Aza)], decitabine, or valproic acid (VPA) in both in vitro and in vivo malignant glioma models to determine if they improved the efficacy of rQNestin34.5 therapy. RESULTS: The use of demethylating agents, such as 5-Aza, improved OV replication and tumor cell lysis in vitro and, in fact, synergized pharmacologically on Chou-Talalay analysis. In vivo, the combination of the demethylating agents, 5-Aza or decitabine, with rQNestin34.5 significantly prolonged the survivorship of athymic mice harboring intracranial human glioma xenografts over single agent alone. CONCLUSION: These results, thus, provide further justification for the exploration of demethylating agents when combined with the OV, rQNestin34.5, in preclinical therapeutics and, possibly, clinical trials for malignant glioma.


Assuntos
Azacitidina/farmacologia , Metilação de DNA/efeitos dos fármacos , Vetores Genéticos/genética , Glioma/genética , Herpesvirus Humano 1/genética , Vírus Oncolíticos/genética , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ilhas de CpG , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Feminino , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Terapia Genética , Vetores Genéticos/administração & dosagem , Glioma/mortalidade , Glioma/patologia , Glioma/terapia , Humanos , Camundongos , Nestina/genética , Terapia Viral Oncolítica , Regiões Promotoras Genéticas , Proteínas Virais/genética , Replicação Viral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
PLoS One ; 8(8): e71932, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23936533

RESUMO

Recent studies report that STAT3 signaling is a master regulator of mesenchymal transformation of gliomas and that STAT3 modulated genes are highly expressed in the mesenchymal transcriptome of gliomas. A currently studied experimental treatment for gliomas consists of intratumoral injection of oncolytic viruses (OV), such as oncolytic herpes simplex virus type 1 (oHSV). We have described one particular oHSV (rQNestin34.5) that exhibits potent anti-glioma activity in animal models. Here, we hypothesized that alterations in STAT3 signaling in glioma cells may affect the replicative ability of rQNestin34.5. In fact, human U251 glioma cells engineered to either over-express STAT3 or with genetic down-regulation of STAT3 supported oHSV replication to a significantly higher or lesser degree, respectively, when compared to controls. Administration of pharmacologic agents that increase STAT3 phosphorylation/activation (Valproic Acid) or increase STAT3 levels (Interleukin 6) also significantly enhanced oHSV replication. Instead, administration of inhibitors of STAT3 phosphorylation/activation (LLL12) significantly reduced oHSV replication. STAT3 led to a reduction in interferon signaling in oHSV infected cells and inhibition of interferon signaling abolished the effect of STAT3 on oHSV replication. These data thus indicate that STAT3 signaling in malignant gliomas enhances oHSV replication, likely by inhibiting the interferon response in infected glioma cells, thus suggesting avenues for possible potentiation of oncolytic virotherapy.


Assuntos
Neoplasias Encefálicas/virologia , Glioma/virologia , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Terapia Viral Oncolítica , Fator de Transcrição STAT3/metabolismo , Replicação Viral , Anticonvulsivantes/farmacologia , Western Blotting , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Proliferação de Células , Terapia Combinada , Glioma/metabolismo , Glioma/terapia , Herpes Simples/genética , Herpes Simples/terapia , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Luciferases/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Células Tumorais Cultivadas , Ácido Valproico/farmacologia
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