LncRNA TIALD contributes to hepatocellular carcinoma metastasis via inducing AURKA lysosomal degradation.

The N6-methyladenosine (m6A) RNA methyltransferase METTL16 is an emerging player in RNA modification landscape and responsible for the deposition of m6A in a few transcripts. AURKA (aurora kinase A) has been confirmed as an oncogene in cancer development including hepatocellular carcinoma (HCC). Nevertheless, it remains unclear whether METTL16 mediated m6A modification of lncRNAs can regulate AURKA activation in cancer progression. Here we aimed to investigate the functional links between lncRNAs and the m6A modification in AURKA signaling and HCC progression. Here we show that LncRNA TIALD (transcript that induced AURKA Lysosomal degradation) was down-regulated in HCC tissues by METTL16 mediated m6A methylation to facilitate its RNA degradation, and correlates with poor prognosis. Functional assays reveal that TIALD inhibits HCC metastasis both in vitro and in vivo. Mechanistically, TIALD directly interacts with AURKA and facilitate its degradation through the lysosomal pathway to inhibited EMT and metastasis of HCC. AURKA's specific inhibitor alisertib exerts effective therapeutic effect on liver cancer with low TIALD expression, which might provide a new insight into HCC therapy. Our study uncovers a negative functional loop of METTL16-TIALD-AURKA axis, and identifies a new mechanism for METTL16 mediated m6A-induced decay of TIALD on AURKA signaling in HCC progression, which may provide potential prognostic and therapeutic targets for HCC.

Enhancing mesenchymal stem cell survival and homing capability to improve cell engraftment efficacy for liver diseases.

Although mesenchymal stem cell (MSC) transplantation provides an alternative strategy for end-stage liver disease (ESLD), further widespread application of MSC therapy is limited owing to low cell engraftment efficiency. Improving cell engraftment efficiency plays a critical role in enhancing MSC therapy for liver diseases. In this review, we summarize the current status and challenges of MSC transplantation for ESLD. We also outline the complicated cell-homing process and highlight how low cell engraftment efficiency is closely related to huge differences in extracellular conditions involved in MSC homing journeys ranging from constant, controlled conditions in vitro to variable and challenging conditions in vivo. Improving cell survival and homing capabilities enhances MSC engraftment efficacy. Therefore, we summarize the current strategies, including hypoxic priming, drug pretreatment, gene modification, and cytokine pretreatment, as well as splenectomy and local irradiation, used to improve MSC survival and homing capability, and enhance cell engraftment and therapeutic efficiency of MSC therapy. We hope that this review will provide new insights into enhancing the efficiency of MSC engraftment in liver diseases.

Navoximod modulates local HSV-1 replication to reshape tumor immune microenvironment for enhanced immunotherapy via an injectable hydrogel.

Oncolytic virotherapy can lead to tumor lysis and systemic anti-tumor immunity, but the therapeutic potential in humans is limited due to the impaired virus replication and the insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). To solve the above problems, we identified that Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor Navoximod promoted herpes simplex virus type 1 (HSV-1) replication and HSV-1-mediated oncolysis in tumor cells, making it a promising combination modality with HSV-1-based virotherapy. Thus, we loaded HSV-1 and Navoximod together in an injectable and biocompatible hydrogel (V-Navo@gel) for hepatocellular carcinoma (HCC) virotherapy. The hydrogel formed a local delivery reservoir to maximize the viral replication and distribution at the tumor site with a single-dose injection. Notably, V-Navo@gel improved the disease-free survival time of HCC- bearing mice and protects the mice against tumor recurrence. What's more, V-Navo@gel also showed an effective therapeutic efficacy in the rabbit orthotopic liver cancer model. Mechanistically, we further discovered that our combination strategy entirely reprogramed the TME through single-cell RNA sequencing. All these results collectively indicated that the combination of Navoximod with HSV-1 could boost the viral replication and reshape TME for tumor eradication through the hydrogel reservoir.

Genome Sequence of Cluster BI1 Streptomyces griseus Phage TaidaOne.

Bacteriophage TaidaOne was isolated from soil collected in Taipei, Taiwan, using the host Streptomyces griseus. It is a siphovirus with a 56,183-bp genome that contains 86 protein-coding genes. Based on gene content similarity, it was assigned to actinobacteriophage subcluster BI1, within which only TaidaOne and GirlPower genomes contain an acetyltransferase homolog gene.

NIR-II Ratiometric Chemiluminescent/Fluorescent Reporters for Real-Time Monitoring and Evaluating Cancer Photodynamic Therapy Efficacy.

The development of probes for early monitoring tumor therapy response may greatly benefit the promotion of photodynamic therapy (PDT) efficacy. Singlet oxygen (1 O2 ) generation is a typical indicator for evaluating PDT efficacy in cancer. However, most existing probes cannot quantitatively detect 1 O2 in vivo due to the high reactivity and transient state, and thus have a poor correlation with PDT response. Herein, a 1 O2 -responsive theranostic platform comprising thiophene-based small molecule (2SeFT-PEG) and photosensitizer Chlorin e6 (Ce6) micelles for real-time monitoring PDT efficacy is developed. After laser irradiation, the Ce6-produced 1 O2 could simultaneously kill cancer and trigger 2SeFT-PEG to produce increased chemiluminescence (CL) and decreased fluorescence (FL) signals variation at 1050 nm in the second near-infrared (NIR-II, 950-1700 nm) window. Significantly, the ratiometric NIR-II CL/FL imaging at 1050 nm could effectively quantify and monitor the concentration of 1 O2 and O2 consumption or recovery, so as to evaluate the therapeutic efficacy of PDT in vivo. Hence, this 1 O2 activated NIR-II CL/FL probe provides an efficient ratiometric optical imaging platform for real-time evaluating PDT effect and precisely guiding the PDT process in vivo.

Far-Red Light Triggered Production of Bispecific T Cell Engagers (BiTEs) from Engineered Cells for Antitumor Application.

Bispecific T-cell engagers (BiTEs), which have shown potent antitumor activity in humans, are emerging as one of the most promising immunotherapeutic strategies for cancer treatment in recent years. However, the clinical application of BiTEs nowadays has been hampered by their short half-life in the circulatory system due to their low molecular weight and rapid renal clearance. Inevitable continuous infusion of BiTEs has become a routine operation in order to achieve effective treatment, although it is costly, inconvenient, time-consuming, and even painful for patients in some cases. To develop an on-demand, tunable, and reversible approach to overcome these limitations, we assembled a transcription-control device into mammalian cells based on a bacterial far-red light (FRL) responsive signaling pathway to drive the expression of a BiTE against Glypican 3 (GPC3), which is a highly tumor-specific antigen expressed in most hepatocellular carcinomas (HCC). As demonstrated in in vitro experiments, we proved that the FRL sensitive device spatiotemporally responded to the control of FRL illumination and produced a therapeutic level of BiTEs that recruited and activated human T cells to eliminate GPC3 positive tumor cells. By functionally harnessing the power of optogenetics to remotely regulate the production of BiTEs from bioengineered cells and demonstrating its effectiveness in treating tumor cells, this study provides a novel approach to achieve an in vivo supply of BiTEs, which could be potentially applied to other formats of bispecific antibodies and facilitate their clinical applications.

Remodeling Tumor-Associated Neutrophils to Enhance Dendritic Cell-Based HCC Neoantigen Nano-Vaccine Efficiency.

Hepatocellular carcinoma (HCC) commonly emerges in an immunologically "cold" state, thereafter protects it away from cytolytic attack by tumor-infiltrating lymphocytes, resulting in poor response to immunotherapy. Herein, an acidic/photo-sensitive dendritic cell (DCs)-based neoantigen nano-vaccine has been explored to convert tumor immune "cold" state into "hot", and remodel tumor-associated neutrophils to potentiate anticancer immune response for enhancing immunotherapy efficiency. The nano-vaccine is constructed by SiPCCl2 -hybridized mesoporous silica with coordination of Fe(III)-captopril, and coating with exfoliated membrane of matured DCs by H22-specific neoantigen stimulation. The nano-vaccines actively target H22 tumors and induce immunological cell death to boost tumor-associated antigen release by the generation of excess 1 O2 through photodynamic therapy, which act as in situ tumor vaccination to strengthen antitumor T-cell response against primary H22 tumor growth. Interestingly, the nano-vaccines are also home to lymph nodes to directly induce the activation and proliferation of neoantigen-specific T cells to suppress the primary/distal tumor growth. Moreover, the acidic-triggered captopril release in tumor microenvironment can polarize the protumoral N2 phenotype neutrophils to antitumor N1 phenotype for improving the immune effects to achieve complete tumor regression (83%) in H22-bearing mice and prolong the survival time. This work provides an alternative approach for developing novel HCC immunotherapy strategies.

Tracking Cell Viability for Adipose-Derived Mesenchymal Stem Cell-Based Therapy by Quantitative Fluorescence Imaging in the Second Near-Infrared Window.

Cell survival rate determines engraftment efficiency in adipose-derived mesenchymal stem cell (ADSC)-based regenerative medicine. In vivo monitoring of ADSC viability to achieve effective tissue regeneration is a major challenge for ADSC therapy. Here, we developed an activated near-infrared II (NIR-II) fluorescent nanoparticle consisting of lanthanide-based down-conversion nanoparticles (DCNPs) and IR786s (DCNP@IR786s) for cell labeling and real-time tracking of ADSC viability in vivo. In dying ADSCs due to excessive ROS generation, absorption competition-induced emission of IR786s was destroyed, which could turn on the NIR-II fluorescent intensity of DCNPs at 1550 nm by 808 nm laser excitation. In contrast, the NIR-II fluorescent intensity of DCNPs was stable at 1550 nm by 980 nm laser excitation. This ratiometric fluorescent signal was precise and sensitive for tracking ADSC viability in vivo. Significantly, the nanoparticle could be applied to quantitively evaluate stem cell viability in real-time in vivo. Using this method, we successfully sought two small molecules including glutathione and dexamethasone that could improve stem cell engraftment efficiency and enhance ADSC therapy in a liver fibrotic mouse model. Therefore, we provide a potential strategy for real-time in vivo quantitative tracking of stem cell viability in ADSC therapy.

NIR-II Fluorescent Biodegradable Nanoprobes for Precise Acute Kidney/Liver Injury Imaging and Therapy.

NIR-II fluorescent nanoprobes based on inorganic materials, including rare-earth-doped nanoparticles, single-walled carbon nanotubes, CdS quantum dots (QDs), gold nanoclusters, etc., have gained growing interest in bioimaging applications. However, these nanoprobes are usually not biodegradable and lack therapeutic functions. Herein, we developed novel NIR-II fluorescence (FL) imaging and therapeutic nanoprobes based on black phosphorus QDs (BPQDs), which exhibited excellent biodegradability and high tunability of size-dependent optical properties. By adjusting the size of nanoparticles, BPQDs can specifically accumulate in the kidney or liver. Importantly, a low dosage of BPQDs can effectively protect tissues from reactive oxygen species (ROS)-mediated damage in acute kidney and liver injury, which was real-time monitored by responsive NIR-II fluorescence imaging. Overall, we developed novel NIR-II emitting and therapeutic BPQDs with excellent biodegradability vivo, providing a promising candidate for NIR-II FL imaging and ROS scavenging.

Site-Specific Biomimicry of Antioxidative Melanin Formation and Its Application for Acute Liver Injury Therapy and Imaging.

Biocompatible nano-antioxidants composed of natural molecules/materials, such as dopamine and melanin, are of great interest for diverse biomedical applications. However, the lack of understanding of the precise structure of these biomaterials and thus the actual dose of effective components impedes their advancement to translation. Herein, a strategy to mimic in situ melanin formation and explore its antioxidative applications is reported, by developing a PEGylated, phenylboronic-acid-protected L-DOPA precursor (PAD) that can self-assemble into well-defined nanoparticles (PADN). Exposure to oxidative species leads to deprotection of phenylboronic acids, transforming PADN to PEG-L-DOPA, which, similar to the biosynthetic pathway of melanin, can be oxidized and polymerized into an antioxidative melanin-like structure. With ultrahigh stability and superior antioxidative activity, the PADN shows remarkable efficacy in prevention and treatment of acute liver injury/failure. Moreover, the in situ structure transformation enables PADN to visualize damaged tissue noninvasively by photoacoustic imaging. Overall, a bioinspired antioxidant with precise structure and site-specific biological activity for theranostics of oxidative stress-related diseases is described.

In Vivo Tracking of Cell Viability for Adoptive Natural Killer Cell-Based Immunotherapy by Ratiometric NIR-II Fluorescence Imaging.

The therapeutic efficacy of natural killer (NK) cells-based immunotherapy is greatly related with the survival of transplanted NK cells. However, no effective strategy was reported to monitor NK cell viability in adoptive immunotherapy in vivo. Herein, we develop a ratiometric NIR-II fluorescence imaging strategy to quantitively track and visualize the adoptive NK cell viability in vivo in real-time. The nanoprobe consists of lanthanide-based down-conversion nanoparticles (DCNP) coated with IR786s, a reactive oxygen species (ROS) sensitive to NIR dye, which was directly labeled with NK cells. Upon cell death, the excessive ROS generation occurred within NK cells, along with IR786s degradation, turning on NIR-II fluorescent signal at 1550 nm of DCNP under 808-nm excitation, while the fluorescent signal at 1550 nm of DCNP under 980-nm excitation was stable. Such an intracellular ROS-induced ratiometric NIR-II fluorescent signal was validated to correlate well with NK cell viability in vivo. Using this nanoreporter, we further demonstrated that co-treatment with IL-2, IL-15, and IL-21 could improve NK cell viability in vivo, achieving enhanced immunotherapy for orthotopic hepatocellular carcinoma. Overall, this strategy allows for longitudinal and quantitative tracking of NK cell viability in NK cell-based immunotherapy.

NIR-II Photoacoustic Reporter for Biopsy-Free and Real-Time Assessment of Wilson's Disease.

Wilson's disease (WD) is a rare inherited disorder of copper metabolism with pathological copper hyperaccumulation in some vital organs. However, the clinical diagnosis technique of WD is complicated, aggressive, and time-consuming. In this work, a novel ratiometric photoacoustic (PA) imaging nanoprobe in the NIR-II window is developed to achieve noninvasive, rapid, and accurate Cu2+ quantitative detection in vitro and in vivo. The nanoprobe consists of Cu2+ -responsive IR970 dye and a nonresponsive palladium-coated gold nanorod (AuNR-Pd), achieving a concentration-dependent ratiometric PA970 /PA1260 signal change. The urinary Cu2+ content is detectable within minutes down to a detection limit of 76 × 10-9 m. This report acquisition time is several orders of magnitude shorter than those of existing detection approaches requiring complex procedure. Moreover, utilizing the ratiometric PA nanoprobe, PA imaging enables biopsy-free measurement of the liver Cu2+ content and visualization of the liver Cu2+ biodistribution of WD patient, which avoid the body injury during the clinical Cu2+ test using liver biopsy method. The NIR-II ratiometric PA detection method is simple and noninvasive with super precision, celerity, and simplification, which holds great promise as an alternative to liver biopsy for clinical diagnosis of WD.

Enhancing therapeutic effects and in vivo tracking of adipose tissue-derived mesenchymal stem cells for liver injury using bioorthogonal click chemistry.

Adipose tissue-derived mesenchymal stem cell (ADSC)-based therapy is attractive for liver diseases, but the long-term therapeutic outcome is still far from satisfaction due to the low hepatic engraftment efficiency of ADSC transplantation. Herein, we propose a strategy based on liver sinusoidal endothelial cell (LSEC)-targeting peptide modification and near infrared (NIR) fluorescent probe labeling for enhancing LSEC-barrier-migration ability and in vivo tracking of ADSCs in a liver injury mouse model. RLTRKRGLK (RK), a LSEC-targeted peptide, and indocyanine green (ICG), a FDA approved infrared fluorescent dye, were simultaneously modified on the ADSC surface via a bioorthogonal click reaction. The equipped ADSCs not only exhibited significant binding ability towards LSEC both in vitro and in vivo, but could also be monitored by NIR imaging in vivo. In particular, the RK-modified ADSCs showed remarkable higher hepatic accumulation as compared to unmodified ADSCs, resulting in better therapeutic outcomes. Therefore, this study provides a simple and convenient method for enhancing the homing of transplanted ADSCs to injured liver accompanying with in vivo cell tracking ability, which may shed light on accelerating the clinical translation of the ADSC-based therapy for liver diseases.

Antioxidant preconditioning improves therapeutic outcomes of adipose tissue-derived mesenchymal stem cells through enhancing intrahepatic engraftment efficiency in a mouse liver fibrosis model.

BACKGROUND: Although it has been preclinically suggested that adipose tissue-derived mesenchymal stem cell (ADSC)-based therapy could effectively treat chronic liver diseases, the hepatic engraftment of ADSCs is still extremely low, which severely limits their long-term efficacy for chronic liver diseases. This study was designed to investigate the impact of antioxidant preconditioning on hepatic engraftment efficiency and therapeutic outcomes of ADSC transplantation in liver fibrotic mice. METHODS: Liver fibrosis model was established by using intraperitoneal injection of carbon tetrachloride (CCl4) in the male C57BL/6 mice. Subsequently, the ADSCs with or without antioxidant pretreatment (including melatonin and reduced glutathione (GSH)) were administrated into fibrotic mice via tail vein injection. Afterwards, the ADSC transplantation efficiency was analyzed by ex vivo imaging, and the liver functions were assessed by biochemical analysis and histopathological examination, respectively. Additionally, a typical hydrogen peroxide (H2O2)-induced cell injury model was applied to mimic the cell oxidative injury to further investigate the protective effects of antioxidant preconditioning on cell migration, proliferation, and apoptosis of ADSCs. RESULTS: Our data showed that antioxidant preconditioning could enhance the therapeutic effects of ADSCs on liver function recovery by reducing the level of AST, ALT, and TBIL, as well as the content of hepatic hydroxyproline and fibrotic area in liver tissues. Particularly, we also found that antioxidant preconditioning could enhance hepatic engraftment efficiency of ADSCs in liver fibrosis model through inhibiting oxidative injury. CONCLUSIONS: Antioxidant preconditioning could effectively improve therapeutic effects of ADSC transplantation for liver fibrosis through enhancing intrahepatic engraftment efficiency by reducing oxidative injuries. These findings might provide a practical strategy for enhancing ADSC transplantation and therapeutic efficiency.

High expression levels of CLEC4M indicate poor prognosis in patients with hepatocellular carcinoma.

The identification of novel and accurate biomarkers is important to improve the prognosis of patients with hepatocellular carcinoma (HCC). C-Type lectin domain family 4 member M (CLEC4M) is involved in the progression of numerous cancer types. However, the clinical significance of CLEC4M in HCC is yet to be elucidated. The aim of the present study is to evaluate the involvement of CLEC4M in HCC progression. The expression level of CLEC4M was determined in tumor, and their corresponding adjacent non-tumor tissues derived from 88 patients with HCC, using immunohistochemistry, western blot and reverse transcription-quantitative PCR. The correlation between CLEC4M expression and certain clinicopathological characteristics was retrospectively analyzed. The results suggested that CLEC4M was specifically labeled in sinusoidal endothelial cells, in both HCC and non-tumor tissues. Moreover, the expression of CLEC4M in tumor tissues was significantly lower than that in non-tumor tissues (P<0.0001), which indicated its potential as a biomarker of the development of HCC. Subsequently, correlation analysis suggested that the relatively higher CLEC4M expression in HCC tissues was significantly associated with increased microvascular invasion (P=0.008), larger tumor size (P=0.018), absence of tumor encapsulation (P<0.0001) and lower tumor differentiation (P=0.019). Notably, patients with high CLEC4M expression levels in their tumor tissues experienced more frequent recurrence and shorter overall survival (OS) times compared with the low-expression group. Furthermore, CLEC4M expression in tumor tissues was identified as an independent and significant risk factor for recurrence-free survival and OS. The results of the present study suggest that CLEC4M may be a valuable biomarker for the prognosis of the patients with HCC, postoperatively.

MT1G serves as a tumor suppressor in hepatocellular carcinoma by interacting with p53.

Poor prognosis of hepatocellular carcinoma (HCC) patients is frequently associated with rapid tumor growth, recurrence and drug resistance. MT1G is a low-molecular weight protein with high affinity for zinc ions. In the present study, we investigated the expression of MT1G, analyzed clinical significance of MT1G, and we observed the effects of MT1G overexpression on proliferation and apoptosis of HCC cell lines in vitro and in vivo. Our results revealed that MT1G was significantly downregulated in tumor tissues, and could inhibit the proliferation as well as enhance the apoptosis of HCC cells. The mechanism study suggested that MT1G increased the stability of p53 by inhibiting the expression of its ubiquitination factor, MDM2. Furthermore, MT1G also could enhance the transcriptional activity of p53 through direct interacting with p53 and providing appropriate zinc ions to p53. The modulation of MT1G on p53 resulted in upregulation of p21 and Bax, which leads cell cycle arrest and apoptosis, respectively. Our in vivo assay further confirmed that MT1G could suppress HCC tumor growth in nude mice. Overall, this is the first report on the interaction between MT1G and p53, and adequately uncover a new HCC suppressor which might have therapeutic values by diminishing the aggressiveness of HCC cells.

Inflammatory Micro-environment Contributes to Stemness Properties and Metastatic Potential of HCC via the NF-κB/miR-497/SALL4 Axis.

Increasing evidence has demonstrated the essential role of inflammatory micro-environment in tumorigenesis and tumor progression. Some cancer cells in tumor maintain typical stemness properties and, with the capacity of self-renewal, are thought to be crucial for the initiation and maintenance of tumors as well as their metastasis. Although both inflammatory micro-environment and stemness properties played crucial roles in tumor initiation and development, currently it is still unclear whether and how the inflammatory micro-environment promotes cancer stemness properties. Here, we show the first evidence that the inflammatory micro-environment promotes the stemness properties and metastatic potential of hepatocellular carcinoma (HCC) via the NF-κB/miR-497/SALL4 axis. We discover that miR-497 directly targets SALL4, negatively regulates its expression, and further inhibits the self-renewal and metastasis of HCC; more importantly, inflammatory factor TNF-α inhibits the expression of miR-497 via NF-kB-mediated negative transcriptional regulation and simultaneously upregulates the expression of SALL4 and promotes the self-renewal and metastasis phenotypes of HCC cells. Moreover, lower expression of miR-497 is significantly associated with poor prognosis in HCC patients. Taken together, our findings not only revealed a novel signaling pathway (NF-κB/miR-497/SALL4 axis) to connect inflammation with stemness properties, and clarified the molecular mechanisms underlying the inflammation-mediated self-renewal and metastasis phenotypes, but also provided novel molecular targets for developing new anticancer strategies.

Antioxidants inhibit cell senescence and preserve stemness of adipose tissue-derived stem cells by reducing ROS generation during long-term in vitro expansion.

BACKGROUND: Adipose tissue-derived mesenchymal stem cells (ADSCs) are promising candidates for regenerative medicine. However, long-term in vitro passaging leads to stemness loss and cell senescence of ADSCs, resulting in failure of ADSC-based therapy. METHODS: In this study, ADSCs were treated with low dose of antioxidants (reduced glutathione and melatonin) with anti-aging and stem cell protection properties in the in vitro passaging, and the cell functions including stem cell senescence, cell migration, cell multidirectional differentiation potential, and ROS content were carefully analyzed. RESULTS: We found that GSH and melatonin could maintain ADSC cell functions through reducing cell senescence and promoting cell migration, as well as by preserving stemness and multidirectional differentiation potential, through inhibiting ROS generation during long-term expansion of ADSCs. CONCLUSIONS: Our results suggested that antioxidant treatment could efficiently prevent the dysfunction and preserve cell functions of ADSCs after long-term passaging, providing a practical strategy to facilitate ADSC-based therapy.

An Optogenetic Controllable T Cell System for Hepatocellular Carcinoma Immunotherapy.

Rationale: T-cell based immunotherapy increasingly shows broad application prospects in cancer treatment, but its performance in solid tumors is far from our expectation, partly due to the re-inhibition of infiltrated T cells by immunosuppressive tumor microenvironment. Here we presented an artificial synthetic optogenetic circuit to control the immune responses of engineered T cells on demand for promoting and enhancing the therapeutic efficiency of cancer immunotherapy. Methods: We designed and synthesized blue-light inducible artificial immune signaling circuit and transgene expression system. The blue light triggered transgene expression was investigated by luciferase activity assay, qPCR and ELISA. The in vitro cytotoxicity and proliferation assays were carried out on engineered T cells. The in vivo anti-tumor activity of engineered T cells was investigated on xenograft model of human hepatocellular carcinoma. Results: Blue light stimulation could spatiotemporally control gene expression of specific cytokines (IL2, IL15, and TNF-α) in both engineered 293T cells and human primary T cells. This optogenetic engineering strategy significantly enhanced the expansion ability and cytolytic activity of primary T cells upon light irradiation, and the light activated T cells showed high-efficiency of elimination against xenograft of hepatocellular carcinoma cells. Conclusions: The current study represented an engineered remotely control T cell system for solid tumor treatment, and provided a potential strategy to partially overcome the intrinsic shortages of current immune cell therapy.

High expression of B7­H2 or B7­H3 is associated with poor prognosis in hepatocellular carcinoma.

B7 family members have been associated with the signaling transduction pathways underlying tumor immune evasion in hepatocellular carcinoma. In the present study, associations between the clinical characteristics of patients with hepatocellular carcinoma (HCC) and the expression of B7­H2 and B7­H3 were analyzed. A total of 63 formalin­fixed and paraffin­embedded HCC tissues were collected to be used as a tissue microarray. Following this, the association between B7­H2/B7­H3 and the prognosis of patients with HCC was analyzed using Pearson's χ2 test, the Kaplan­Meier method and receiver operating characteristic curve analysis. The results demonstrated that the expression of B7­H2 was significantly associated with recurrence (within 1 year) in patients with HCC (P<0.01), and that the expression of B7­H3 was associated with recurrence (within 1 year), metastasis and 2­year overall survival rate in patients with HCC (P<0.01, P=0.036 and P=0.016, respectively). In addition, the combined expression of B7­H2 and B7­H3 was associated with prognostic factors, including recurrence (within 1 year) and survival rate (within 2 years), in patients with HCC. In particular, an increased area under the curve was achieved when the combined expression of B7­H2 and B7­H3 was considered, compared with that for α­fetoprotein. Taken together, these results indicated that B7­H2­ and/or B7­H3­positive expression indicates a poor clinical outcome for patients, and the combination of B7­H2 and B7­H3 may be a preferential prognostic biomarker in patients with HCC.