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Trabectedin Promotes Oncolytic Virus Antitumor Efficacy, Viral Gene Expression, and Immune Effector Function in Models of Bone Sarcoma

ABSTRACT: Trabectedin Promotes Oncolytic Virus Antitumor Efficacy, Viral Gene Expression, and Immune Effector Function in Models of Bone Sarcoma

PROVIDER: PRJNA1082199 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28162618_1.fastq.gz	Fastqsanger.gz
	SRR28162618_2.fastq.gz	Fastqsanger.gz
	SRR28162619_1.fastq.gz	Fastqsanger.gz
	SRR28162619_2.fastq.gz	Fastqsanger.gz
	SRR28162620_1.fastq.gz	Fastqsanger.gz

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Trabectedin Promotes Oncolytic Virus Antitumor Efficacy, Viral Gene Expression, and Immune Effector Function in Models of Bone Sarcoma

Project description:We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular antiviral response which increases viral transcript presence in the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing infiltrating immunosuppressive CD4 T and myeloid cells and stimulating granzyme expression in infiltrating T and natural killer cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.

2024-10-11 | GSE260551 | GEO

Oncolytic ORFV induces antitumor immunity

Project description:Oncolytic ORFV induces antitumor immunity

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Thymosin α1 reverses oncolytic adenovirus-induced M2 polarization of macrophages to improve antitumor immunity and therapeutic efficacy

Project description:Although oncolytic adenoviruses have been widely studied for their direct oncolytic activity and immunomodulatory role in cancer immunotherapy, the immunosuppressive feedback loop induced by oncolytic adenoviruses remains poorly studied. Here, we showed that type V adenovirus (ADV) induces the polarization of tumor-associated macrophages (TAMs) to the M2 phenotype and increases the infiltration of regulatory T cells (Tregs) in the tumor microenvironment (TME). By selectively compensating for these deficiencies, Tα1 reprogrammed “M2-like” TAMs toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity. Moreover, ADVTα1 was constructed by harnessing the merits of all the components for the aforementioned combinatorial therapy. Both in vitro and in vivo data showed that both exogenously supplied and adenovirus-produced Tα1 orchestrate TAM reprogramming and enhance the antitumor efficacy of ADV via CD8+ T cells, showing promising prospects for clinical translation. Our findings provide inspiration for improving oncolytic adenovirus combination therapy and designing new oncolytic engineered adenoviruses.

2024-07-04 | GSE271202 | GEO

Thymosin α1 reverses oncolytic adenovirus-induced M2 polarization of macrophages to improve antitumor immunity and therapeutic efficacy

2024-06-28 | GSE271046 | GEO

Doxorubicin Hydrochloride or Trabectedin in Treating Patients With Previously Untreated Advanced or Metastatic Soft Tissue Sarcoma

Project description:RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride and trabectedin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether trabectedin is more effective than doxorubicin hydrochloride in treating patients with advanced or metastatic soft tissue sarcoma. PURPOSE: This randomized phase II/III trial is studying the safety of trabectedin compared with doxorubicin hydrochloride and to see how well they work in treating patients with advanced or metastatic soft tissue sarcoma.

| 2094138 | ecrin-mdr-crc

Oncolytic ORFV induces antitumor immunity

Project description:To study the oncolytic effect of ORFV on tumors, we performed ORFV treatment (i.t.) in B16 engrafted tumors, changes of gene transcripts were detected

2022-12-09 | GSE206634 | GEO

Oncolytic virus M1 functions as a bi-functional checkpoint inhibitor to enhance the antitumor activity of DC vaccine

Project description:Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic viruses are considered to be an ideal strategy to overcome immunosuppression and expose TAAs, therefore they may work synergistically with DC vaccines. In this study, we demonstrated that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccine in a variety of syngeneic tumor mouse models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we identified that tumor cells offset the function of DC vaccines through the myeloid immune checkpoint SIRPα-CD47, while OVM can downregulate the expression of SIRPα and CD47 in DCs and tumor cells, respectively. Based on the fact that OVM upregulates the expression of PD-L1 in DCs, PD-L1 blockade was introduced with the combination of DC vaccines and OVM, resulting in a further potentiation of antitumor activity. Overall, we revealed that OVM can strengthen the antitumor efficacy of DC vaccines by targeting the immune checkpoint SIRPα-CD47 axis, which exerts dominant immunosuppressive effects on DC vaccines.

2023-09-01 | GSE222080 | GEO

Combination therapy with oncolytic virus and adoptively transferred T cells or mRNA vaccine amplifies antitumor effects [scRNA-Seq]

Project description:Adoptive T-cell therapy or oncolytic virotherapy has made significant progress, but the efficacy was limited by the lack of infiltration into solid tumors when used alone. Here, an oncolytic virus (rVSV-LCMVG) was designed and combined with adoptively transferred T cells. By turning cold tumors hot, in B16 tumor-bearing mice, combination therapy showed superior antitumor effects than monotherapy, whether rVSV-LCMVG was administered intratumorally or intravenously. Combination therapy significantly increased cytokine and chemokine levels within tumors and sensitized refractory tumors by boosting T-cell recruitment, down-regulating the expression of PD1, and restoring effector-T cell function. To offer a combination therapy with greater translational value, mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells, and exhibited comparable amplified anti-tumor effects. This study proposed a rational combination therapy of oncolytic virus with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens, in terms of synergistic efficacy and mechanism.

2024-03-15 | GSE235290 | GEO

Combination therapy with oncolytic virus and adoptively transferred T cells or mRNA vaccine amplifies antitumor effects [RNA-Seq]

2024-03-15 | GSE235289 | GEO

Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: Relevance for their antitumor activity

Project description:In recent years, it has been recognized the central role of cell bioenergetics in regulating immune cell function and fate giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Immunometabolism has been studied in the modulation of macrophage polarization. Thus, early metabolic changes associated with the polarisation of macrophages into pro-inflammatory or pro-resolving cells under different stimuli have been characterized. Tumour-associated macrophages are among the most abundant cells in the tumour microenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, a systems biology approach that integrates transcriptomics and metabolomics unveils the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two intercalating DNA agents with proved antitumor activity in the low nanomolar range. Our results show that TRB and LUR activate human macrophages towards a pro-inflammatory functional phenotype by inducing a specific metabolic rewiring program that includes ROS production and changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, TCA cycle serine and methylglyoxal pathways in human macrophages. glutamine, aspartate, histidine, and proline consumption are increased whereas 50 nM TRB increases lactate release and oxygen consumption is depressed . The observed immunometabolic rewiring could explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer.

2023-06-25 | GSE235390 | GEO

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