Background: 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. Methods: Gene expression data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Immune cell infiltration was determined by single-sample Gene Set Enrichment Analysis (ssGSEA) depending on the integrated immune gene sets from published studies. Univariate analysis was used to determine the prognostic value of the infiltrated immune cells. Least absolute shrinkage and selection operator (LASSO) regression was performed to screen for the most survival-relevant immune cells. An immune-cell characteristic score (ICCS) model was constructed by using multivariate Cox regression analysis. Results: The immune cell infiltration patterns across 32 cancer types were identified, and patients in the high immune cell infiltration cluster had worse overall survival (OS) but better progression-free interval (PFI) compared to the low immune cell infiltration cluster. However, immune cell infiltration showed inconsistent prognostic value depending on the cancer type. High immune cell infiltration (High CI) indicated a worse prognosis in brain lower grade glioma (LGG), glioblastoma multiforme (GBM), and uveal melanoma (UVM), and favorable prognosis in adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), sarcoma (SARC), and skin cutaneous melanoma (SKCM). LUAD prognosis was significantly influenced by the infiltration of 13 immune cell types, with high infiltration of all but Type 2 T helper (Th2) cells correlating with a favorable prognosis. The ICCS model based on six most survival-relevant immune cell populations was generated that classified patients into low- and high-ICCS groups with good and poor prognoses, respectively. The multivariate and stratified analyses further revealed that the ICCS was an independent prognostic factor for LUAD. Conclusions: The infiltration of immune cells in 32 cancer types was quantified, and considerable heterogeneity was observed in the prognostic relevance of these cells in different cancer types. An ICCS model was constructed for LUAD with competent prognostic performance, which can further deepen our understanding of the TME of LUAD and can have implications for immunotherapy.

A series of epichlorohydrin-cross-linked hydroxyethyl cellulose/soy protein isolate composite films (EHSF) was fabricated from hydroxyethyl cellulose (HEC) and soy protein isolate (SPI) using a process involving blending, cross-linking, solution casting, and evaporation. The films were characterized with FTIR, solid-state (13)C NMR, UV-vis spectroscopy, and mechanical testing. The results indicated that cross-linking interactions occurred in the inter- and intramolecules of HEC and SPI during the fabrication process. The EHSF films exhibited homogeneous structure and relative high light transmittance, indicating there was a certain degree of miscibility between HEC and SPI. The EHSF films exhibited a relative high mechanical strength in humid state and an adjustable water uptake ratio and moisture absorption ratio. Cytocompatibility, hemocompatibility and biodegradability were evaluated by a series of in vitro and in vivo experiments. These results showed that the EHSF films had good biocompatibility, hemocompatibility, and anticoagulant effect. Furthermore, EHSF films could be degraded in vitro and in vivo, and the degradation rate could be controlled by adjusting the SPI content. Hence, EHSF films might have a great potential for use in the biomedical field.

BackgroundIn 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.MethodsThrough homologous recombination with the parental VV, an engineered VV-scFv-TIGIT was produced, which encodes a single-chain variable fragment (scFv) targeting T-cell immunoglobulin and ITIM domain (TIGIT). The antitumor efficacy of the VV-scFv-TIGIT was explored in several subcutaneous and ascites tumor models. The antitumor efficacy of VV-scFv-TIGIT combined with programmed cell death 1 (PD-1) or lymphocyte-activation gene 3 (LAG-3) blockade was also investigated.ResultsThe VV-scFv-TIGIT effectively replicated in tumor cells and lysed them, and prompt the infected tumor cells to secret the functional scFv-TIGIT. Compared with control VV, intratumoral injection of VV-scFv-TIGIT in several mouse subcutaneous tumor models showed superior antitumor efficacy, accompanied by more T cell infiltration and a higher degree of CD8+ T cells activation. Intraperitoneal injection of VV-scFv-TIGIT in a mouse model of malignant ascites also significantly improved T cell infiltration and CD8+ T cell activation, resulting in more than 90% of the tumor-bearing mice being cured. Furthermore, the antitumor immune response induced by VV-scFv-TIGIT was dependent on CD8+ T cells which mediated a long-term immunological memory and a systemic antitumor immunity against the same tumor. Finally, the additional combination of PD-1 or LAG-3 blockade further enhanced the antitumor efficacy of VV-scFv-TIGIT, increasing the complete response rate of tumor-bearing mice.ConclusionsOncolytic virotherapy using engineered VV-scFv-TIGIT was an effective strategy for cancer immunotherapy. Administration of VV-scFv-TIGIT caused a profound reshaping of the suppressive tumor microenvironment from ‘cold’ to ‘hot’ status. VV-scFv-TIGIT also synergized with PD-1 or LAG-3 blockade to achieve a complete response to tumors with poor response to VV or immune checkpoint blockade monotherapy.

Borna disease virus (BDV) is one of the infectious agents that causes diseases of the central nervous systemin a wide range of vertebrate species and, perhaps, in humans. The phosphoprotein (P) of BDV, an essential cofactor of virus RNA-dependent RNA polymerase, is required for virus replication. In this study, we identified the gamma-aminobutyric acid receptor-associated protein (GABARAP) with functions in neurobiology as one of the viral P protein-interacting cellular factors by using an approach of phage display-based protein-protein interaction analysis. Direct binding between GABARAP and P protein was confirmed by coimmunoprecipitation, protein pull-down, and mammalian two-hybrid analyses. GABARAP originally was identified as a linker between the gamma-aminobutyric acid receptor (GABAR) and the microtubule to regulate receptor trafficking and plays important roles in the regulation of the inhibitory neural transmitter gamma-aminobutyric acid (GABA). We showed that GABARAP colocalizes with P protein in the cells infected with BDV or transfected with the P gene, which resulted in shifting the localization of GABARAP from the cytosol to the nucleus. We further demonstrated that P protein blocks the trafficking of GABAR, a principal GABA-gated ion channel that plays important roles in neural transmission, to the surface of cells infected with BDV or transfected with the P gene. We proposed that during BDV infection, P protein binds to GABARAP, shifts the distribution of GABARAP from the cytoplasm to the nucleus, and disrupts the trafficking of GABARs to the cell membranes, which may result in the inhibition of GABA-induced currents and in the enhancement of hyperactivity and anxiety.Borna disease virus (BDV), a nonsegmental negative-strand RNA virus, belongs to the Bornaviridae family and is characterized by low productivity, neurotropism, and the nuclear localization of transcription and replication (12,33). BDV was reported to cause diseases of the central nervous system (CNS) in sheep and horses originally and then in a wide range of other vertebrate species (25). Epidemiological studies have shown that a higher prevalence of BDV infection was found in psychiatric patients than in controls, indicating that BDV is a potential human pathogen related to psychiatric diseases (1, 19). In contrast, some reports suggested that BDV does not play significant roles in human health (9, 36).One of the most prominent features of BDV infection is the heavy inflammatory reaction in the CNS and the rare degeneration of neurons in naturally infected hosts (25). In experimentally infected rats, the histopathology of the CNS is dependent on the immune status of the host at the time of inoculation, the genetic background, and the route of infection (33). The inoculation of immunocompetent adult rats with BDV results in marked immune-mediated meningoencephalitis consistent with the classical Borna disease. In the process of the persistent infection of BDV in adult rats, the degeneration of the neurons is observed. In contrast, i...

Hepatitis C virus (HCV) infection is one of the major causes of hepatocellular carcinoma (HCC). It has been demonstrated that the overexpression of angiogenic factors are associated with the maintenance of liver neoplasia. Hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) are important regulators of angiogenesis and are important in wound healing, the regeneration of new vessels and reproductive functions. The present study investigated the role of the HCV core protein in the induction of HIF-1α and VEGF expression. The HCV core gene and HIF-1α siRNA were transfected into Huh7.5.1 cells. The results demonstrated that the induction of HCV core gene expression in Huh7.5.1 cells leads to the overexpression and stabilization of HIF-1α, and the activation of HIF-1α leads, in turn, to the stimulation of VEGF, which is one of the most important angiogenic factors. These results provide new information to facilitate the understanding of HCC oncogenesis.