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Reprograming responsiveness of tolerogenic CD8+ T cells using a CXCR4 antagonist-armed oncolytic virus requires reversal of M2 macrophage polarization

ABSTRACT: Overcoming barriers to the generation of antitumor immunity to self-and neo-antigens is a central concern of cancer immunotherapy. This study investigated the effect of interactions between ovarian cancer (OC) cells and the tumor microenvironment (TME) on the ability of oncolytic virotherapy to activate responsiveness of self antigen-specific and neoantigen-specific CD8+ T lymphocytes in tolerogenic and wild-type (WT) murine tumor models, respectively

ORGANISM(S): Mus musculus

PROVIDER: GSE199880 | GEO | 2022/06/30

REPOSITORIES: GEO

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Reprograming responsiveness of tolerogenic CD8+ T cells using a CXCR4 antagonist-armed oncolytic virus requires reversal of M2 macrophage polarization

Project description:Reprograming responsiveness of tolerogenic CD8+ T cells using a CXCR4 antagonist-armed oncolytic virus requires reversal of M2 macrophage polarization

| PRJNA821883 | ENA

Single-cell RNA sequencing reveals a strong connection between Gadd45g upregulation and oncolytic HSV infection in tumor tissue

Project description:The oncolytic effect of virotherapy derives from the intrinsic capability of the applied virus in selectively infecting and killing tumor cells. Although oncolytic viruses of various constructions have been shown to efficiently infect and kill tumor cells in vitro, the efficiency of these viruses to exert the same effect on tumor cells within tumor tissues in vivo has not been extensively investigated. Here we report our studies using single-cell RNA sequencing to comprehensively analyze the gene expression profile of tumor tissues following herpes simplex virus 2-based oncolytic virotherapy. Our data revealed the extent and cell types within the tumor microenvironment that could be infected by the virus. Moreover, we observed changes in the expression of cellular genes, including antiviral genes, in response to viral infection. One notable gene found to be upregulated significantly in oncolytic virus-infected tumor cells was Gadd45g, which is desirable for optimal virus replication. These results not only help reveal the precise infection status of the oncolytic virus in vivo, but also provide insight that may lead to the development of new strategies to further enhance the therapeutic efficacy of oncolytic virotherapy.

2021-10-31 | GSE186753 | GEO

Combination of oncolytic Maraba virus with immune checkpoint blockade overcomes therapy resistance in an immunologically cold model of advanced melanoma with dysfunctional T cell receptor signalling

Project description:Oncolytic viruses are promising immunotherapeutic agents, but their efficacy, particularly following intra-tumoural injection, in relation to the size of the targeted tumour, is unclear. Here we show that an oncolytic rhabdovirus, maraba, activates an immune response in human as well as mouse pre-clinical systems, which targets viral as well as tumour-associated antigens. The addition of immune checkpoint blockade to virotherapy is apparent only on the treatment of larger tumours, which have an inherently more immunosuppressive tumour microenvironment, including skewing of T cell receptor engagement with antigen from conventional to regulatory CD4+ cells. Maraba converts the immunologically cold tumour to hot, thus priming the tumour microenvironment for effective αPD1 combination therapy. This study supports the use of maraba oncolytic virotherapy in combination with immune checkpoint inhibitors in melanoma and highlights the impact of the tumour burden on the immune microenvironment and benefit of single agent and combination treatment.

2024-08-08 | GSE270746 | GEO

Pevonedistat sensitizes cancer cells to oncolytic VSVd51 virotherapy

Project description:Pevonedistat sensitizes cancer cells to oncolytic VSVd51 virotherapy

| PRJNA850784 | ENA

Effect of human DAI expressed by an oncolytic vaccinia virus on the gene expression of tumor cells (HS294T) and monocytes (THP-1).

2016-03-01 | GSE76208 | 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

Effect of human DAI expressed by an oncolytic vaccinia virus on the gene expression of tumor cells (HS294T) and monocytes (THP-1).

Project description:Human melanoma tumor cells (HS294T) and monocytes (THP-1) were infected with a double deleted (-VGF, -TK) oncolytic vaccinia virus expressing human DAI (DNA-dependent activator of interferon-regulatory factors). Total RNA was collected and gene expresson profiles were determined with Agilent microarray. An oncolytic vaccinia virus that does not express DAI was used to control the effect of DAI and uninfected cells (PBS treated) were used to control the effect of virus infection. In oncolytic virotherapy the ability of the virus to activate the immune system against tumors is nowadays generally understood to be a key mechanism in full eradication of cancer and for long-term anti-tumor effects. We armed an oncolytic vaccinia virus with DAI to increase the immunogenicity and the vaccine potency of the virus. The aim of this study was to study if the expression of DAI by a replicating vaccinia virus would alter the gene expression profile of infected cells and to study what are the differentially expressed genes. Three-condition experiment: vvdd-tdTomato-hDAI vs. vvdd-tdTomato vs. PBS treated cells. 2 cell lines: HS294T tumor cells and THP-1 monocytes. 3 biological replicates of virus infected cells per cell line and 2 uninfected replicates per cell line. HS294T and THP-1 cells were treated with vvdd-tdTomato-hDAI or vvdd-tdTomato control virus, or with PBS only to have an uninfected control. 16 hours after infection total RNA was extracted and whole genome gene pfofiles were analyzed and differentially expressed genes determined.

2016-03-01 | E-GEOD-76208 | biostudies-arrayexpress

Subclone of resistant CT26 murine tumor shows high sensitivity to VA7 virotherapy: A novel system to study innate immunity and antigen dominance in oncolytic immuno-virotherapy

Project description:Recently, attenuated Semliki Forest virus vector VA7 completely eliminated type I interferon (IFN) unresponsive human U87 glioma xenografts while IFN responsive mouse GL261 and CT-2A gliomas proved refractory to the oncolytic virotherapy. Here we describe in two clones of a well established Balb/c mouse tumor cell line, CT26 murine colon carcinoma, diametrically opposed IFN responsiveness and sensitivity to oncolytic virus. Both CT26WT and CT26LacZ clones secreted biologically active type I IFN in vitro upon infection but virus replication was self-limiting only in CT26WT cells. Total transcriptome sequencing (RNA-Seq) and western blotting experiments revealed that in sharp contrast to CT26LacZ cells, CT26WT cells had strong constitutive expression of 56 different genes associated with pattern recognition and type I interferon signaling pathways, spanning two reported anti-RNA virus gene signatures and22 genes that have been reported to have direct anti-Alphaviral activity. Correspondingly, only CT26LacZ tumors were infectable in vivo, resulting in rapid central necrosis of the tumors by 96 hours post infection and complete tumor eradication both in immunocompetent and in SCID mice. CT26LacZ tumor eradication by oncolysis induced 100% protective immunity against homologous CT26LacZ challenge but only 50% protection against heterologous CT26WT challenge, indicating LacZ immune dominance over shared antigens. We believe the two clone CT26 system described herein constitutes a challenging yet realistic model for clonally and immunologically heterogeneous cancer where a strong therapy efficacy bias toward sensitive tumor subpopulations might falsely predict therapeutic success on a broad patient scale highlighting the necessity of successful pre-screening for responsive tumors. RNA-Seq in CT26 tumor cell line

2014-09-05 | E-GEOD-53001 | biostudies-arrayexpress

More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway

Project description:Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell‑intrinsic functions in immune and cancer cells. In line with these studies, here we show that PD-L1 potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cells resulted in enhanced infection with oncolytic viruses in cancer cells in vitro and in vivo. PD-L1 expression marks tumor explants from cancer patients that are best infected by oncolytic viruses. Agonistic antibodies targeting PD-L1 further reduced type I IFN responses and enhanced oncolytic virus infection. Mechanistically, PD-L1 suppressed type I interferon by promoting Warburg metabolism, characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD‑L1‑expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.

2023-06-28 | GSE210884 | GEO

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