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1.
BMC Cancer ; 22(1): 400, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35418059

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most common high-grade malignant brain tumour in adults and arises from the glial cells in the brain. The prognosis of treated GBM remains very poor with 5-year survival rates of 5%, a figure which has not improved over the last few decades. Currently, there is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. HOX gene dysregulation is now a widely recognised feature of many malignancies. METHODS: In this study we have focused on HOX gene dysregulation in GBM as a potential therapeutic target in a disease with high unmet need. RESULTS: We show significant dysregulation of these developmentally crucial genes and specifically that HOX genes A9, A10, C4 and D9 are strong candidates for biomarkers and treatment targets for GBM and GBM cancer stem cells. We evaluated a next generation therapeutic peptide, HTL-001, capable of targeting HOX gene over-expression in GBM by disrupting the interaction between HOX proteins and their co-factor, PBX. HTL-001 induced both caspase-dependent and -independent apoptosis in GBM cell lines. CONCLUSION: In vivo biodistribution studies confirmed that the peptide was able to cross the blood brain barrier. Systemic delivery of HTL-001 resulted in improved control of subcutaneous murine and human xenograft tumours and improved survival in a murine orthotopic model.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Genes Homeobox , Glioblastoma/tratamento farmacológico , Glioblastoma/terapia , Humanos , Camundongos , Peptídeos/genética , Distribuição Tecidual
2.
Proc Natl Acad Sci U S A ; 111(6): 2265-70, 2014 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-24469818

RESUMO

Because cytokine-priming signals direct CD8(+) T cells to acquire unique profiles that affect their ability to mediate specific immune responses, here we generated IL-9-skewed CD8(+) T (Tc9) cells by priming with Th9-polarized condition. Compared with type-I CD8(+) cytotoxic T (Tc1) cells, Tc9 secreted different cytokines and were less cytolytic in vitro but surprisingly elicited greater antitumor responses against advanced tumors in OT-I/B16-OVA and Pmel-1/B16 melanoma models. After adoptive transfer, Tc9 cells persisted longer and differentiated into IFN-γ- and granzyme-B (GrzB)-producing cytolytic Tc1-like effector cells. Phenotypic analysis revealed that adoptively transferred Tc9 cells secreted IL-2 and were KLRG-1(low) and IL-7Rα(high), suggesting that they acquired a signature of "younger" phenotype or became long-term lived cells with capacity of self-renewal. Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo. These findings have clinical implications for the improvement of CD8(+) T-cell-based adoptive immunotherapy of cancers.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva , Interleucina-9/biossíntese , Melanoma Experimental/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Ciclofosfamida/farmacologia , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Interferon gama/biossíntese , Melanoma Experimental/terapia , Camundongos
3.
J Cell Mol Med ; 20(8): 1550-60, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27028905

RESUMO

Mesenchymal stem cells (MSCs) possess an immunoregulatory capacity and are a therapeutic target for many inflammation-related diseases. However, the detailed mechanisms of MSC-mediated immunosuppression remain unclear. In this study, we provide new information to partly explain the molecular mechanisms of immunoregulation by MSCs. Specifically, we found that A20 expression was induced in MSCs by inflammatory cytokines. Knockdown of A20 in MSCs resulted in increased proliferation and reduced adipogenesis, and partly reversed the suppressive effect of MSCs on T cell proliferation in vitro and inhibited tumour growth in vivo. Mechanistic studies indicated that knockdown of A20 in MSCs inhibited activation of the p38 mitogen-activated protein kinase (MAPK) pathway, which potently promoted the production of tumour necrosis factor (TNF)-α and inhibited the production of interleukin (IL)-10. Collectively, these data reveal a crucial role of A20 in regulating the immunomodulatory activities of MSCs by controlling the expression of TNF-α and IL-10 in an inflammatory environment. These findings provide novel insights into the pathogenesis of various inflammatory-associated diseases, and are a new reference for the future development of treatments for such afflictions.


Assuntos
Células-Tronco Mesenquimais/imunologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Adipogenia , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Diferenciação Celular , Proliferação de Células , Forma Celular , Citocinas/metabolismo , Dinoprostona/metabolismo , Técnicas de Silenciamento de Genes , Terapia de Imunossupressão , Mediadores da Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , RNA Interferente Pequeno/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
4.
Int J Cancer ; 136(1): 34-43, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24806617

RESUMO

p38 MAPK signaling controls cell growth, proliferation and the cell cycle under stress conditions. However, the function of p38 activation in tumor metastasis is still not well understood. We report that p38 activation in breast cancer cells inhibits tumor metastasis but does not substantially modulate primary tumor growth. Stable p38 knockdown in breast cancer cells suppressed NF-κB p65 activation, inhibiting miR-365 expression and resulting in increased IL-6 secretion. The inhibitory effect of p38 signaling on metastasis was mediated by suppression of mesenchymal stem cell (MSC) migration to the primary tumor and sites of metastasis, where MSCs can differentiate into cancer-associated fibroblasts to promote tumor metastasis. The migration of MSCs to these sites relies on CXCR4-SDF1 signaling in the tumor microenvironment. Analysis of human primary and metastatic breast cancer tumors showed that p38 activation was inversely associated with IL-6 and vimentin expression. This study suggests that combination analysis of p38 MAPK and IL-6 signaling in patients with breast cancer may improve prognosis and treatment of metastatic breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias Pulmonares/enzimologia , Células-Tronco Mesenquimais/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Animais , Apoptose , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CXCL12/metabolismo , Feminino , Fibroblastos/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/metabolismo , Neoplasias Pulmonares/secundário , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos BALB C , MicroRNAs/metabolismo , Transplante de Neoplasias , Receptores CXCR4/metabolismo , Microambiente Tumoral , Vimentina/metabolismo
5.
Mol Cancer ; 13: 132, 2014 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-24884733

RESUMO

BACKGROUND: Interferon (IFN)-γ-mediated immune response plays an important role in tumor immunosurveillance. However, the regulation of IFN-γ-mediated tumorigenesis and immune response remains elusive. USP18, an interferon stimulating response element, regulates IFN-α-mediated signaling in anti-viral immune response, but its role in IFN-γ-mediated tumorigenesis and anti-tumor immune response is unknown. METHOD: In this study, USP18 in tumorigenesis and anti-tumor immune response was comprehensively appraised in vivo by overexpression or downregulation its expression in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice. RESULTS: Ectopic expression or downregulation of USP18 in B16 melanoma tumor cells inhibited or promoted tumorigenesis, respectively, in immunocompetent mice. USP18 expression in B16 melanoma tumor cells regulated IFN-γ-mediated immunoediting, including upregulating MHC class-I expression, reducing tumor cell-mediated inhibition of T cell proliferation and activation, and suppressing PD-1 expression in CD4+ and CD8+ T cells in tumor-bearing mice. USP18 expression in B16 melanoma tumor cells also enhanced CTL activity during adoptive immunotherapy by prolonging the persistence and enhancing the activity of adoptively transferred CTLs and by reducing CTL exhaustion in the tumor microenvironment. Mechanistic studies demonstrated that USP18 suppressed tumor cell-mediated immune inhibition by activating T cells, inhibiting T-cell exhaustion, and reducing dendritic cell tolerance, thus sensitizing tumor cells to immunosurveillance and immunotherapy. CONCLUSION: These findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response.


Assuntos
Carcinogênese/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Interferon gama/imunologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Ubiquitina Tiolesterase/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Carcinogênese/genética , Carcinogênese/patologia , Proliferação de Células , Citotoxicidade Imunológica , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Inata , Imunoterapia Adotiva , Interferon gama/genética , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Transplante de Neoplasias , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Citotóxicos/transplante , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ubiquitina Tiolesterase/genética
6.
Int J Cancer ; 135(5): 1132-41, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24474467

RESUMO

Our previous studies showed that anti-ß2M monoclonal antibodies (mAbs) at high doses have direct apoptotic effects on myeloma cells, suggesting that anti-ß2M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the ability of the mAbs at much lower concentrations to indirectly kill myeloma cells by utilizing immune effector cells or molecules. Our results showed that anti-ß2M mAbs effectively lysed MM cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which were correlated with and dependent on the surface expression of ß2M on MM cells. The presence of MM bone marrow stromal cells or addition of IL-6 did not attenuate anti-ß2M mAb-induced ADCC and CDC activities against MM cells. Furthermore, anti-ß2M mAbs only showed limited cytotoxicity toward normal B cells and nontumorous mesenchymal stem cells, indicating that the ADCC and CDC activities of the anti-ß2M mAbs were more prone to the tumor cells. Lenalidomide potentiated in vitro ADCC activity against MM cells and in vivo tumor inhibition capacity induced by the anti-ß2M mAbs by enhancing the activity of NK cells. These results support clinical development of anti-ß2M mAbs, both as a monotherapy and in combination with lenalidomide, to improve MM patient outcome.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Apoptose/imunologia , Mieloma Múltiplo/terapia , Microglobulina beta-2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Antígenos de Superfície/imunologia , Proliferação de Células , Proteínas do Sistema Complemento/imunologia , Humanos , Fatores Imunológicos/farmacologia , Interleucina-6/imunologia , Lenalidomida , Masculino , Células-Tronco Mesenquimais/imunologia , Camundongos , Camundongos SCID , Mieloma Múltiplo/imunologia , Interferência de RNA , RNA Interferente Pequeno , Talidomida/análogos & derivados , Talidomida/farmacologia , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Microglobulina beta-2/antagonistas & inibidores , Microglobulina beta-2/genética
7.
Cancer Immunol Immunother ; 63(8): 835-45, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24841535

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells to initiate immune responses, and DC survival time is important for affecting the strength of T-cell responses. Interleukin (IL)-9-producing T-helper (Th)-9 cells play an important role in anti-tumor immunity. However, it is unclear how Th9 cells communicate with DCs. In this study, we investigated whether murine Th9 cells affected the survival of myeloid DCs. DCs derived from bone marrow of C57BL/6 mice were cocultured with Th9 cells from OT-II mice using transwell, and the survival of DCs was examined. DCs cocultured with Th9 cells had longer survival and fewer apoptotic cells than DCs cultured alone in vitro. In melanoma B16-OVA tumor-bearing mice, DCs conditioned by Th9 cells lived longer and induced stronger anti-tumor response than control DCs did in vivo. Mechanistic studies revealed that IL-3 but not IL-9 secreted by Th9 cells was responsible for the prolonged survival of DCs. IL-3 upregulated the expression of anti-apoptotic protein Bcl-xL and activated p38, ERK and STAT5 signaling pathways in DCs. Taken together, our data provide the first evidence that Th9 cells can promote the survival of DCs through IL-3, and will be helpful for designing Th9 cell immunotherapy and more effective DC vaccine for human cancers.


Assuntos
Células Dendríticas/imunologia , Imunoterapia Adotiva/métodos , Interleucina-9/imunologia , Melanoma Experimental/terapia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Sobrevivência Celular/imunologia , Técnicas de Cocultura , Células Dendríticas/citologia , Humanos , Interleucina-3/biossíntese , Interleucina-3/imunologia , Masculino , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/citologia
8.
Mol Ther Oncolytics ; 29: 30-41, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37114074

RESUMO

Longstanding evidence implicate glioma stem-like cells as the main drivers contributing toward glioblastoma (GBM) therapy resistance and tumor recurrence. Although oncolytic herpes simplex virus (oHSV) viral therapy is a promising biological therapy recently approved for melanoma (in the United States and Europe) and GBM (in Japan); however, the impact of this therapy on GBM stem-like cells (GSCs) is understudied. Here we show that post-oHSV virotherapy activated AKT signaling results in an enrichment of GSC signatures in glioma, which mimics the enrichment in GSC observed after radiation treatment. We also uncovered that a second-generation oncolytic virus armed with PTEN-L (oHSV-P10) decreases this by moderating IL6/JAK/STAT3 signaling. This ability was retained in the presence of radiation treatment and oHSV-P10-sensitized intracranial GBM to radiotherapy. Collectively, our findings uncover potential mechanisms to overcome GSC-mediated radiation resistance via oHSV-P10.

9.
Mol Ther Oncolytics ; 28: 171-181, 2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36789106

RESUMO

High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule that plays an important role in inflammation and tumorigenesis. Receptor for advanced glycation end products (RAGE) is one of the major receptors to which extracellular HMGB1 binds to mediate its activity. RAGE is highly expressed on the endothelial cells (ECs) and regulates endothelial permeability during inflammation. Here, we introduced the endogenous secretory form of RAGE (esRAGE) as a decoy receptor for RAGE ligands into an oncolytic herpes simplex virus 1 (oHSV) (OVesRAGE), which, upon release, can function to block RAGE signaling. OVesRAGE significantly decreased phosphorylation of MEK1/2 and Erk and increased cleaved PARP in glioblastoma (GBM) cells in vitro and in vivo. oHSV-infected GBM cells co-cultured with ECs were used to test OVesRAGE effect on EC activation, vessel leakiness, virus replication, and tumor cell killing. OVesRAGE could effectively secrete esRAGE and rescue virus-induced EC migration and activation. Reduced EC activation facilitated virus replication in tumor cells when co-cultured with ECs. Finally, OVesRAGE significantly enhanced therapeutic efficacy in GBM-bearing mice. Collectively, our data demonstrate that HMGB1-RAGE signaling could be a promising target and that its inhibition is a feasible approach to improve the efficacy of oHSV therapy.

10.
J Immunother Cancer ; 11(2)2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36796878

RESUMO

BACKGROUND: Mammalian cells have developed multiple intracellular mechanisms to defend against viral infections. These include RNA-activated protein kinase (PKR), cyclic GMP-AMP synthase and stimulation of interferon genes (cGAS-STING) and toll-like receptor-myeloid differentiation primary response 88 (TLR-MyD88). Among these, we identified that PKR presents the most formidable barrier to oncolytic herpes simplex virus (oHSV) replication in vitro. METHODS: To elucidate the impact of PKR on host responses to oncolytic therapy, we generated a novel oncolytic virus (oHSV-shPKR) which disables tumor intrinsic PKR signaling in infected tumor cells. RESULTS: As anticipated, oHSV-shPKR resulted in suppression of innate antiviral immunity and improves virus spread and tumor cell lysis both in vitro and in vivo. Single cell RNA sequencing combined with cell-cell communication analysis uncovered a strong correlation between PKR activation and transforming growth factor beta (TGF-ß) immune suppressive signaling in both human and preclinical models. Using a murine PKR targeting oHSV, we found that in immune-competent mice this virus could rewire the tumor immune microenvironment to increase the activation of antigen presentation and enhance tumor antigen-specific CD8 T cell expansion and activity. Further, a single intratumoral injection of oHSV-shPKR significantly improved the survival of mice bearing orthotopic glioblastoma. To our knowledge, this is the first report to identify dual and opposing roles of PKR wherein PKR activates antivirus innate immunity and induces TGF-ß signaling to inhibit antitumor adaptive immune responses. CONCLUSIONS: Thus, PKR represents the Achilles heel of oHSV therapy, restricting both viral replication and antitumor immunity, and an oncolytic virus that can target this pathway significantly improves response to virotherapy.


Assuntos
Neoplasias Encefálicas , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Humanos , Camundongos , Neoplasias Encefálicas/patologia , Terapia Viral Oncolítica/métodos , Simplexvirus , Fator de Crescimento Transformador beta , Microambiente Tumoral , eIF-2 Quinase/metabolismo
11.
Mol Ther ; 19(1): 211-7, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20959814

RESUMO

Although the benefits of adoptive T-cell therapy can be increased by prior lymphodepletion of the recipient, this process usually requires chemotherapy or radiation. Vaccination with antigens to which the transferred T cells respond should be a less toxic means of enhancing their activity, but to date such vaccines have not been effective. We, therefore, determined which characteristics an adenoviral vaccine has to fulfill to optimally activate and expand adoptively transferred antigen-specific T cells in vivo. We evaluated (i) antigen, (ii) flagellin, a Toll-like receptor (TLR) 5 ligand, and (iii) an inhibitor of the antigen-presenting attenuator A20. Vaccination of mice before T-cell transfer with a vaccine that contained all three components dramatically enhanced the effector function of ovalbumin (OVA)-specific T cells as judged by the regression of established B16-OVA tumors compared to one- and two-component vaccines. Immunization with the three-component vaccine induced a strong Th1 environment, which was critical for the observed synergy and proved as effective as cytoxan-induced lymphodepletion in enhancing in vivo T-cell expansion. Thus, the combination of our vaccine with T-cell therapy has the potential to enhance and broaden adoptive cellular immunotherapy.


Assuntos
Adenoviridae/imunologia , Vacinas Anticâncer/imunologia , Imunoterapia Adotiva/métodos , Linfócitos T/imunologia , Células Th1/imunologia , Vacinas Virais/imunologia , Animais , Apresentação de Antígeno/imunologia , Antígenos/imunologia , Linhagem Celular , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Flagelina/genética , Imunização Secundária/métodos , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ovalbumina/imunologia , RNA Interferente Pequeno/genética , Vacinas Sintéticas/genética , Vacinas Sintéticas/metabolismo
12.
Viruses ; 14(1)2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35062322

RESUMO

Oncolytic herpes simplex virus (oHSV) is a highly promising treatment for solid tumors. Intense research and development efforts have led to first-in-class approval for an oHSV for melanoma, but barriers to this promising therapy still exist that limit efficacy. The process of infection, replication and transmission of oHSV in solid tumors is key to obtaining a good lytic destruction of infected cancer cells to kill tumor cells and release tumor antigens that can prime anti-tumor efficacy. Intracellular tumor cell signaling and tumor stromal cells present multiple barriers that resist oHSV activity. Here, we provide a review focused on oncolytic HSV and the essential viral genes that allow for virus replication and spread in order to gain insight into how manipulation of these pathways can be exploited to potentiate oHSV infection and replication among tumor cells.


Assuntos
Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Replicação Viral , Animais , Linhagem Celular Tumoral , Herpes Simples , Herpesvirus Humano 1/genética , Humanos , Tropismo
13.
Clin Cancer Res ; 28(7): 1460-1473, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35022322

RESUMO

PURPOSE: Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV-induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus-induced immunotherapy. EXPERIMENTAL DESIGN: RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of patients with recurrent glioblastoma (GBM) treated with oHSV was used to evaluate the effect of NOTCH signaling on virus-induced immunotherapy. RESULTS: TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly correlated with a higher myeloid cell infiltration. Immunofluorescence staining and RNA-seq uncovered a significant induction of Jag1 (NOTCH ligand) expression in infiltrating myeloid cells upon oHSV infection. Jag1-expressing macrophages further spread NOTCH activation in the tumor microenvironment (TME). NOTCH-activated macrophages increased the secretion of CCL2, which further amplified myeloid-derived suppressor cells. CCL2 and IL10 induction was also observed in serum of patients with recurrent GBM treated with oHSV (rQnestin34.5; NCT03152318). Pharmacologic blockade of NOTCH signaling rescued the oHSV-induced immunosuppressive TME and activated a CD8-dependent antitumor memory response, resulting in a therapeutic benefit. CONCLUSIONS: NOTCH-induced immunosuppressive myeloid cell recruitment limited antitumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy.


Assuntos
Glioblastoma , Células Supressoras Mieloides , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Linhagem Celular Tumoral , Glioblastoma/patologia , Humanos , Imunoterapia , Camundongos , Células Supressoras Mieloides/metabolismo , Recidiva Local de Neoplasia/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Simplexvirus , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Adv Cell Gene Ther ; 4(2)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33829146

RESUMO

Oncolytic virotherapy has been tested in numerous early phase clinical studies. However, the antitumor activity of oncolytic viruses thus far has been limited. Numerous strategies are being explored to enhance their antitumor activity by activating the adaptive arm of the immune system. We reasoned that it might also be possible to engineer oncolytic viruses to redirect tumor-associated macrophages to tumor cells for therapeutic benefit. We engineered an oncolytic vaccinia virus (VV) to disrupt the CD47/SIRPα interaction by expressing a chimeric molecule that consists of the ectodomain of SIRPα and the Fc domain of IgG4 (SIRPα-Fc-VV). SIRPα-Fc-VV readily replicated in tumor cells and redirected M1 as well as M2 macrophages to tumor cells in vitro. In contrast, control VVs that either encoded YFP (YFP-VV) or SIRPα (SIRPα-VV) did not. In vivo, SIRPα-Fc-VV had greater antitumor activity than YFP-VV and SIRPα-VV in an immune competent osteosarcoma model resulting in a significant survival advantage. Pretreatment with cytoxan further augmented the antitumor activity of SIRPα-Fc-VV. Thus, arming oncolytic viruses with SIRPα-Fc may present a promising strategy to enhance their antitumor activity for the virotherapy of solid tumors.

15.
Clin Cancer Res ; 27(2): 542-553, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33087329

RESUMO

PURPOSE: Here we investigated the impact of oncolytic herpes simplex virus (HSV) treatment on cisplatin sensitivity of platinum-resistant ovarian cancer, and the impact of the combination on immunotherapy. EXPERIMENTAL DESIGN: Therapeutic efficacy of the combination was assessed in platinum-resistant human and murine ovarian cancer peritoneal metastatic mouse models (n = 9-10/group). RNA sequencing along with flow cytometry of splenocytes from treated mice was employed to examine the effect of antitumor immune response (n = 3/group). Anti-PD-1 antibody was performed to evaluate impact on checkpoint inhibition in vivo. RESULTS: Gene Ontology pathway analysis uncovered disruption of cellular extracellular vesicle (EV)-related pathways in infected cells (FDR = 2.97E-57). Mechanistically, we identified reduced expression of transporters expressed on EV implicated in cisplatin efflux. The increased cisplatin retention led to increased cisplatin-DNA adducts, which resulted in micronuclei and the subsequent activation of cGAS-STING pathway with a significant activation of innate immune cells and translated to an increase in antitumor immunity and efficacy. In mice bearing platinum-resistant ovarian cancer, we also observed a feedback induction of PD-L1 on tumor cells, which sensitized combination-treated mice to anti-PD-1 immune checkpoint therapy. CONCLUSIONS: To our knowledge, this is the first report to show HSV-induced cisplatin retention in infected cells. The consequential increased damaged DNA was then expelled from cells as micronuclei which resulted in induction of inflammatory responses and education of antitumor immunity. The combination therapy also created an environment that sensitized tumors to immune checkpoint therapy.


Assuntos
Cisplatino/uso terapêutico , Terapia Viral Oncolítica/métodos , Neoplasias Ovarianas/terapia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Células Cultivadas , Terapia Combinada , Adutos de DNA/genética , Adutos de DNA/imunologia , Modelos Animais de Doenças , Feminino , Herpesvirus Humano 1/fisiologia , Humanos , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Stem Cells ; 27(7): 1604-15, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19544467

RESUMO

Stem cells are normally maintained in a quiescent state and proliferate only under certain conditions; however, little is known about the biological stimuli that initiate the proliferation and differentiation of stem cells. In this study, we found that functional Toll-like receptors (TLRs) are expressed on mouse embryonic stem (ES) cells and that TLR ligands stimulate ES cell proliferation and promote their hematopoietic differentiation. TLR ligands activate TLR-mediated signaling pathways, leading to the altered expression of numerous genes in ES cells. Moreover, TLR ligands efficiently stimulate the proliferation and expansion of adult stem cells and progenitors of nonhematopoietic tissues, such as mammary glands and intestine as well. We further found that mammary luminal progenitor cells (Lin(-)CD29(+)CD61(+)) express TLR4-MD2 complex and actively proliferate, resulting in the enhanced growth of mammospheres in response to TLR ligands. Thus, mouse ES cells and adult tissue-specific stem cells/progenitors directly sense and respond to microbial products, which function as a class of foreign, but biological stimuli for stem cell/progenitor proliferation. This finding expands the biological role of TLRs and has implications in understanding stem cell biology, tissue repair/homeostasis, and the role of infection and inflammation in malignant transformation.


Assuntos
Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Glândulas Mamárias Animais/citologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Receptores Toll-Like/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células , Células Cultivadas , Células-Tronco Embrionárias/efeitos dos fármacos , Citometria de Fluxo , Imuno-Histoquímica , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Análise de Sequência com Séries de Oligonucleotídeos , Poli I-C/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos
17.
Mol Ther Oncolytics ; 12: 93-102, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30719499

RESUMO

HMGB1 is a ubiquitously expressed intracellular protein that binds DNA and transcription factors and regulates chromosomal structure and function. Under conditions of cell death or stress, it is actively or passively released by cells into the extracellular environment, where it functions as damage-associated molecular pattern (DAMP) that orchestrates pro-inflammatory cytokine release and inflammation. Our results demonstrate that HMGB1 is secreted in the tumor microenvironment after oncolytic HSV (oHSV) infection in vitro and in vivo. The impact of secreted HMGB1 on tumor growth and response to oncolytic viral therapy was evaluated by using HMGB1-blocking antibodies in vitro and in mice bearing intracranial tumors. IVIS and MRI imaging was utilized to visualize in real time virus spread, tumor growth, and changes in edema in mice. Our data showed that HMGB1 released in tumor microenvironment orchestrated increased vascular leakiness and edema. Further HMGB1 blocking antibodies rescued vascular leakiness and enhanced survival of intracranial glioma-bearing mice treated with oHSV.

18.
Neuro Oncol ; 21(9): 1131-1140, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31063549

RESUMO

BACKGROUND: Hyperactivation of the RAS-RAF-MEK-ERK signaling pathway is exploited by glioma cells to promote their growth and evade apoptosis. MEK activation in tumor cells can increase replication of ICP34.5-deleted herpes simplex virus type 1 (HSV-1), but paradoxically its activation in tumor-associated macrophages promotes a pro-inflammatory signaling that can inhibit virus replication and propagation. Here we investigated the effect of blocking MEK signaling in conjunction with oncolytic HSV-1 (oHSV) for brain tumors. METHODS: Infected glioma cells co-cultured with microglia or macrophages treated with or without trametinib were used to test trametinib effect on macrophages/microglia. Enzyme-linked immunosorbent assay, western blotting, and flow cytometry were utilized to evaluate the effect of the combination therapy. Pharmacokinetic (PK) analysis of mouse plasma and brain tissue was used to evaluate trametinib delivery to the CNS. Intracranial human and mouse glioma-bearing immune deficient and immune competent mice were used to evaluate the antitumor efficacy. RESULT: Oncolytic HSV treatment rescued trametinib-mediated feedback reactivation of the mitogen-activated protein kinase signaling pathway in glioma. In vivo, PK analysis revealed enhanced blood-brain barrier penetration of trametinib after oHSV treatment. Treatment by trametinib, a MEK kinase inhibitor, led to a significant reduction in microglia- and macrophage-derived tumor necrosis factor alpha (TNFα) secretion in response to oHSV treatment and increased survival of glioma-bearing mice. Despite the reduced TNFα production observed in vivo, the combination treatment activated CD8+ T-cell mediated immunity and increased survival in a glioma-bearing immune-competent mouse model. CONCLUSION: This study provides a rationale for combining oHSV with trametinib for the treatment of brain tumors.


Assuntos
Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/terapia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Glioblastoma/terapia , Herpesvirus Humano 1 , Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Terapia Viral Oncolítica/métodos , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia , Animais , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glioblastoma/imunologia , Glioma/imunologia , Glioma/terapia , Humanos , Imunocompetência , Macrófagos/imunologia , Camundongos , Microglia/imunologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Células RAW 264.7 , Taxa de Sobrevida , Fator de Necrose Tumoral alfa/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Nat Commun ; 9(1): 5006, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30479334

RESUMO

Engineered oncolytic viruses are used clinically to destroy cancer cells and have the ability to boost anticancer immunity. Phosphatase and tensin homolog deleted on chromosome 10 loss is common across a broad range of malignancies, and is implicated in immune escape. The N-terminally extended isoform, phosphatase and tensin homolog deleted on chromosome 10 alpha (PTENα), regulates cellular functions including protein kinase B signaling and mitochondrial adenosine triphosphate production. Here we constructed HSV-P10, a replicating, PTENα expressing oncolytic herpesvirus, and demonstrate that it inhibits PI3K/AKT signaling, increases cellular adenosine triphosphate secretion, and reduces programmed death-ligand 1 expression in infected tumor cells, thus priming an adaptive immune response and overcoming tumor immune escape. A single dose of HSV-P10 resulted in long term survivors in mice bearing intracranial tumors, priming anticancer T-cell immunity leading to tumor rejection. This implicates HSV-P10 as an oncolytic and immune stimulating therapeutic for anticancer therapy.


Assuntos
Herpesviridae/metabolismo , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Vírus Oncolíticos/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Linfócitos T/metabolismo , Animais , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/secundário , Linhagem Celular Tumoral , Feminino , Humanos , Imunidade , Cinética , Camundongos , Modelos Biológicos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo
20.
JCI Insight ; 3(3)2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29415891

RESUMO

BACKGROUND: DC-based tumor vaccines have had limited clinical success thus far. SOCS1, a key inhibitor of inflammatory cytokine signaling, is an immune checkpoint regulator that limits DC immunopotency. METHODS: We generated a genetically modified DC (gmDC) vaccine to perform immunotherapy. The adenovirus (Ad-siSSF) delivers two tumor-associated antigens (TAAs), survivin and MUC1; secretory bacterial flagellin for DC maturation; and an RNA interference moiety to suppress SOCS1. A 2-stage phase I trial was performed for patients with relapsed acute leukemia after allogenic hematopoietic stem cell transplantation: in stage 1, we compared the safety and efficacy between gmDC treatment (23 patients) and standard donor lymphocyte infusion (25 patients); in stage 2, we tested the efficacy of the gmDC vaccine for 12 acute myeloid leukemia (AML) patients with early molecular relapse. RESULTS: gmDCs elicited potent TAA-specific CTL responses in vitro, and the immunostimulatory activity of gmDC vaccination was demonstrated in rhesus monkeys. A stage 1 study established that this combinatory gmDC vaccine is safe in acute leukemia patients and yielded improved survival rate. In stage 2, we observed a complete remission rate of 83% in 12 relapsed AML patients. Overall, no grade 3 or grade 4 graft-versus-host disease incidence was detected in any of the 35 patients enrolled. CONCLUSIONS: This study, with combinatory modifications in DCs, demonstrates the safety and efficacy of SOCS1-silenced DCs in treating relapsed acute leukemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT01956630. FUNDING: National Institute of Health (R01CA90427); the Key New Drug Development and Manufacturing Program of the "Twelfth Five-Year Plan" of China (2011ZX09102-001-29); and Clinical Application Research of Beijing (Z131107002213148).


Assuntos
Vacinas Anticâncer/administração & dosagem , Células Dendríticas/imunologia , Leucemia Mieloide Aguda/terapia , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adenoviridae/genética , Adolescente , Adulto , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Engenharia Celular/métodos , Criança , Células Dendríticas/transplante , Feminino , Seguimentos , Vetores Genéticos/genética , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunoterapia Adotiva/métodos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Transfusão de Linfócitos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
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