In situ blockade of TNF-TNFR2 axis via oncolytic adenovirus improves antitumor efficacy in solid tumors.

Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME).

Oncolytic adenovirus encoding apolipoprotein A1 suppresses metastasis of triple-negative breast cancer in mice.

Background: Dysregulation of cholesterol metabolism is associated with the metastasis of triple-negative breast cancer (TNBC). Apolipoprotein A1 (ApoA1) is widely recognized for its pivotal role in regulating cholesterol efflux and maintaining cellular cholesterol homeostasis. However, further exploration is needed to determine whether it inhibits TNBC metastasis by affecting cholesterol metabolism.

An oncolytic vaccinia virus encoding hyaluronidase reshapes the extracellular matrix to enhance cancer chemotherapy and immunotherapy.

Background: The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs. Oncolytic viruses (OVs) are being studied extensively for cancer therapy either alone or in conjunction with chemotherapy and immunotherapy. Here, we designed a novel recombinant vaccinia virus encoding a soluble version of hyaluronidase Hyal1 (OVV-Hyal1) to degrade the HA and investigated its antitumor effects in combination with chemo drugs, polypeptide, immune cells, and antibodies.

NatD epigenetically activates FOXA2 expression to promote breast cancer progression by facilitating MMP14 expression.

N-α-acetyltransferase D (NatD) mediates N-α-terminal acetylation of histone H4 (Nt-Ac-H4), but its role in breast cancer metastasis remains unknown. Here, we show that depletion of NatD directly represses the expression of FOXA2, and is accompanied by a significant reduction in Nt-Ac-H4 enrichment at the FOXA2 promoter. We show that NatD is commonly upregulated in primary breast cancer tissues, where its expression level correlates with FOXA2 expression, enhanced invasiveness, and poor clinical outcomes.

Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma.

The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity.

Oncolytic vaccinia virus expressing a bispecific T-cell engager enhances immune responses in EpCAM positive solid tumors.

Insufficient intratumoral T-cell infiltration and lack of tumor-specific immune surveillance in tumor microenvironment (TME) hinder the progression of cancer immunotherapy. In this study, we explored a recombinant vaccinia virus encoding an EpCAM BiTE (VV-EpCAM BiTE) to modulate the immune suppressive microenvironment to enhance antitumor immunity in several solid tumors. VV-EpCAM BiTE effectively infected, replicated and lysed malignant cells.

Metabolic-related gene pairs signature analysis identifies ABCA1 expression levels on tumor-associated macrophages as a prognostic biomarker in primary IDH glioblastoma.

Background: Although isocitrate dehydrogenase (IDH) mutation serves as a prognostic signature for routine clinical management of glioma, nearly 90% of glioblastomas (GBM) patients have a wild-type IDH genotype (IDH) and lack reliable signatures to identify distinct entities.

Methods: To develop a robust prognostic signature for IDH GBM patients, we retrospectively analyzed 4 public datasets of 377 primary frozen tumor tissue transcriptome profiling and clinical follow-up data. Samples were divided into a training dataset (204 samples) and a validation (173 samples) dataset.

Distinguishing the pros and cons of metabolic reprogramming in oncolytic virus immunotherapy.

Oncolytic viruses (OVs) represent a class of cancer immunotherapies that rely on hijacking the host cell factory for replicative oncolysis and eliciting immune responses for tumor clearance. An increasing evidence suggests that the metabolic state of tumor cells and immune cells is a putative determinant of the efficacy of cancer immunotherapy. However, how therapeutic intervention with OVs affects metabolic fluxes within the tumor microenvironment (TME) remains poorly understood.

An engineered oncolytic vaccinia virus encoding a single-chain variable fragment against TIGIT induces effective antitumor immunity and synergizes with PD-1 or LAG-3 blockade.

Background: In addition to directly lysing tumors, oncolytic viruses also induce antitumor immunity by recruiting and activating immune cells in the local tumor microenvironment. However, the activation of the immune cells induced by oncolytic viruses is always accompanied by high-level expression of immune checkpoints in these cells, which may reduce the efficacy of the oncolytic viruses. The aim of this study is to arm the oncolytic vaccinia virus (VV) with immune checkpoint blockade to enhance its antitumor efficacy.

Recombinant adenovirus expressing the fusion protein PD1PVR improves CD8 T cell-mediated antitumor efficacy with long-term tumor-specific immune surveillance in hepatocellular carcinoma.

Purpose: Treatment-associated upregulation of suppressive checkpoints and a lack of costimulatory signals compromise the antitumor efficacy of oncolytic virus immunotherapy. Therefore, we aimed to identify highly effective therapeutic targets to provide a proof-of-principle for immune checkpoint together with oncolytic virus-mediated viro-immunotherapy for cancer.

Methods: A fusion protein containing both the extracellular domain of programmed death-1 (PD-1) and the poliovirus receptor (PVR) was designed.

Enhanced antitumor efficacy of a novel oncolytic vaccinia virus encoding a fully monoclonal antibody against T-cell immunoglobulin and ITIM domain (TIGIT).

Background: Oncolytic virotherapy with vaccinia virus (VV) can lead to effective anti-tumor immunity by turning "cold" tumors into "hot" tumors. However, its therapeutic potential is affected by the tumor's local immunosuppressive tumor microenvironment (TME). Therefore, it is necessary to explore the use of immune checkpoint inhibitors to arm oncolytic VVs to enhance their anti-tumor efficacy.

Recombinant oncolytic adenovirus expressing a soluble PVR elicits long-term antitumor immune surveillance.

Oncolytic virotherapy (OVT) has been suggested to be effective. However, the suppressive effects of checkpoints and insufficient costimulatory signals limit OVT-induced antitumor immune responses. In this study, we constructed a replicative adenovirus, Ad5sPVR, that expresses the soluble extracellular domain of poliovirus receptor (sPVR).

Extracellular Vesicles-Mimetic Encapsulation Improves Oncolytic Viro-Immunotherapy in Tumors With Low Coxsackie and Adenovirus Receptor.

The oncolytic adenovirus (Adv) exhibited poor infection efficiency in tumor cells with low coxsackie and adenovirus receptor (CAR) on the cell surface, which limits the therapeutic efficacy of the Adv-mediated cancer gene therapy. In addition, the abundant adenovirus neutralizing antibodies also abrogate the viral infection of cancer cells. Therefore, novel strategies are required to overcome these two major hurdles to improve the Adv-mediated cancer virotherapy.

Liraglutide activates nature killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma.

Inflammatory IL-6/STAT3 signaling is constitutively activated in diverse cancers and is associated with malignant cell proliferation, invasion and escape of antitumor immunosurveillance. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is commonly used to treat insulin-resistant diabetes. In this study, for the first time, we showed that liraglutide remarkably improved the antitumor immune responses in hepatocellular carcinoma (HCC).

Pan-Cancer Analysis of Immune Cell Infiltration Identifies a Prognostic Immune-Cell Characteristic Score (ICCS) in Lung Adenocarcinoma.

The tumor microenvironment (TME) consists of heterogeneous cell populations, including malignant cells and nonmalignant cells that support tumor proliferation, invasion, and metastasis through extensive cross talk. The intra-tumor immune landscape is a critical factor influencing patient survival and response to immunotherapy. Gene expression data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases.

Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma.

Background: Oncolytic viro-immunotherapy holds promise for cancer treatment. While immune activation can be robustly triggered by oncolytic viruses, negative feedback is often upregulated in the tumour microenvironment (TME). Lactate accumulation, signal transducer and activator of transcription 3 (STAT3) activation, indoleamine 2,3-dioxygenase 1 (IDO1) expression, and myeloid-derived suppressor cell (MDSC) infiltration coordinate to shape the immunosuppressive TME.

Graphene oxide arms oncolytic measles virus for improved effectiveness of cancer therapy.

Background: Replication-competent oncolytic viruses (OVs) have been proven to be a potent anticancer weapon for clinical therapy. The preexisting neutralizing antibody in patients is a big challenge for oncolytic efficacy of OVs. Graphene oxide sheets (GOS) possess excellent biological compatibility and are easy to decorate for targeted delivery.

Recombinant Adenovirus Expressing a Soluble Fusion Protein PD-1/CD137L Subverts the Suppression of CD8 T Cells in HCC.

Oncolytic viruses are an excellent platform for developing effective strategies in cancer immunotherapy. Several challenges remain in the use of viro-immunotherapy for cancer, such as the lack of costimulatory signals and negative regulation of immune checkpoints. In this study, we designed a novel adenovirus expressing a soluble fusion protein, programmed cell death protein 1 (PD-1)/CD137L, which contains the extracellular domains of PD-1 and CD137L at each terminus (Ad5-PC).

A robust six-gene prognostic signature for prediction of both disease-free and overall survival in non-small cell lung cancer.

Background: The high mortality of patients with non-small cell lung cancer (NSCLC) emphasizes the necessity of identifying a robust and reliable prognostic signature for NSCLC patients. This study aimed to identify and validate a prognostic signature for the prediction of both disease-free survival (DFS) and overall survival (OS) of NSCLC patients by integrating multiple datasets.

Methods: We firstly downloaded three independent datasets under the accessing number of GSE31210, GSE37745 and GSE50081, and then performed an univariate regression analysis to identify the candidate prognostic genes from each dataset, and identified the gene signature by overlapping the candidates.

Fludarabine as an Adjuvant Improves Newcastle Disease Virus-Mediated Antitumor Immunity in Hepatocellular Carcinoma.

In addition to direct oncolysis, oncolytic viruses (OVs) also induce antitumor immunity, also called viro-immunotherapy. Limited viral replication and immune-negative feedback are the major hurdles to effective viro-immunotherapy. In this study, we found that use of an adjuvant of fludarabine, a chemotherapeutic drug for chronic myeloid leukemia, increased the replication of Newcastle disease virus (NDV) by targeting signal transducer and activator of transcription 1 (STAT1), which led to enhanced oncolysis of hepatocellular carcinoma (HCC) cells.

Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reactive oxygen species and suppressing Wnt/beta-catenin pathway.

Background: Hepatocellular carcinoma (HCC) is an aggressive malignant disease with poor prognosis. Recent advances suggest the existence of cancer stem cells (CSCs) within liver cancer, which are considered to be responsible for tumor relapse, metastasis, and chemoresistance. However, novel therapeutic approaches for eradicating CSCs are yet to be established.

Liver-enriched Genes are Associated with the Prognosis of Patients with Hepatocellular Carcinoma.

Tissue-enriched genes are highly expressed in one particular tissue type and represent distinct physiological processes. The dynamic profile of tissue-enriched genes during tumorigenesis and progression remains largely unstudied. Here, we identified tissue-enriched genes from 12 tissue types based on RNA sequencing data from the Cancer Genome Atlas (TCGA), and found that the liver had the largest number of such genes among the 12 tissue types.

CD8 T cells mediate the antitumor activity of frankincense and myrrh in hepatocellular carcinoma.

Background: Tumor-promoting inflammation is an emerging hallmark of cancer, which participates in both cancer progression and immune escape. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer with an extremely poor prognosis. Frankincense and myrrh are anti-inflammation agents commonly used in clinic.

Carrier Cells for Delivery of Oncolytic Measles Virus into Tumors: Determinants of Efficient Loading.

Oncolytic measles virus (OMV) is a promising antitumor agent. However, the presence of anti-measles neutralizing antibodies (NAbs) against the hemagglutinin (H) protein of OMV is a major barrier to the therapeutic application of OMV in clinical practice. In order to overcome this challenge, specific types of cells have been used as carriers for OMV.

Proof-of-principle that a decoy virus protects oncolytic measles virus against neutralizing antibodies.

Background: Attenuated oncolytic measles virus (OMV) is a promising antitumor agent in early-phase clinical trials. However, pre-existing immunity against measles might be a hurdle for OMV therapy.

Methods: OMV was inactivated with short-wavelength ultraviolet light (UV-C).