Oncolytic virus M1 functions as a bifunctional checkpoint inhibitor to enhance the antitumor activity of DC vaccine.

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 virus therapy is an ideal strategy to overcome immunosuppression and expose TAAs; therefore, they may work synergistically with DC vaccines. In this study, we demonstrate that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccines across diverse syngeneic mouse tumor models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we show that tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, while OVM can downregulate SIRPα in DCs and CD47 in tumor cells. Since OVM upregulates PD-L1 in DCs, combining PD-L1 blockade with DC vaccines and OVM further enhances antitumor activity. Overall, OVM strengthens the antitumor efficacy of DC vaccines by targeting the SIRPα-CD47 axis, which exerts dominant immunosuppressive effects on DC vaccines.

Regulating a Zn/Co bimetallic catalyst in a metal-organic framework and oxyhydroxide for improved photoelectrochemical water oxidation.

As one of the most popular photoanode materials, hematite (α-Fe2O3) has obvious advantages in the field of photoelectrochemical water splitting (PEC-WS). However, it is difficult to achieve excellent PEC-WS performance without loading a cocatalyst serving as an electron/hole collector to promote photogenerated carrier separation. In this work, FTO/Sn@α-Fe2O3 photoanodes are modified with ZnCo-ZIF and ZnCoOOH bimetallic catalysts to obtain FTO/Sn@α-Fe2O3/Zn0.5Co0.5-ZIF and FTO/Sn@α-Fe2O3/Zn0.46Co0.54OOH photoanodes. Their photocurrent densities reach 2.6 mA cm-2 and 2.3 mA cm-2 at 1.23 VRHE, respectively. The detailed mechanism studies demonstrate that both ZnCoOOH and ZnCo-ZIF can effectively decrease the transfer resistance, increase the Fe2+/Fe3+ ratio and reduce the charge recombination of the α-Fe2O3 film, which synergistically improves the PEC-WS performance. Compared with ZnCoOOH, the ZnCo-ZIF exhibits better photogenerated carrier transfer efficiency and catalytic performance, which mainly can be attributed to the improved binding energy between the ZnCo-ZIF catalyst and the α-Fe2O3 film. This work provides a simple and feasible strategy for constructing bimetallic catalysts and deepens the understanding of different types of bimetallic catalysts for high-performance PEC-WS systems.

Overcoming resistance to oncolytic virus M1 by targeting PI3K-γ in tumor-associated myeloid cells.

Oncolytic viruses (OVs) have become a category of promising anticancer immunotherapeutic agents over the last decade. However, the fact that many individuals fail to respond to OVs highlights the importance of defining the barely known immunosuppressive mechanisms that lead to treatment resistance. Here we found that the immunosuppression mediated by tumor-associated myeloid cells (TAMCs) directly quenches the antitumor effect of oncolytic virus M1 (OVM). OVM induces myeloid cells to migrate into tumors and strengthens their immunosuppressive phenotypes. Mechanically, tumor cells treated with OVM secrete interleukin-6 (IL-6) to activate the phosphatidylinositol 3-kinase (PI3K)-γ/Akt axis in TAMCs, promoting infiltration of TAMCs and aggravating their inhibition on cytotoxic CD8+ T lymphocytes. Pharmacologically targeting PI3K-γ relieves TAMC-mediated immunosuppression and enhances the efficacy of OVM. Additional treatment with immune checkpoint antibodies eradicates multiple refractory solid tumors and induces potent long-term antitumor immune memory. Our findings indicate that OVM functions as a double-edged sword in antitumor immunity and provide insights into the rationale for liberating T cell-mediated antitumor activity by abolishing TAMC-mediated immunosuppression.

Cytotoxic T lymphocyte-associated protein 4 antibody aggrandizes antitumor immune response of oncolytic virus M1 via targeting regulatory T cells.

Oncolytic virotherapies are perceived as remarkable immunotherapies coming into view and represent highly promising cancer treatments, yet to figure out its specific immune responses and underlying barriers remains critical. Albeit recent studies have demonstrated that oncolytic viruses (OVs) could fine tune tumor microenvironment (TME) to elicit tumor suppression mainly due to effective T-cell responses, the interaction between suppressive T cells and OVs is barely undetermined. Herein, we found that regulatory T cells (Treg cells) were increased in the TME following systemic administration of oncolytic virus M1 along with the higher expression of relative cytokines and chemokines in both mouse RM-1 prostatic carcinoma model and mouse B16F10 melanoma model. Besides, Treg cells expressed high levels of CD25 post-M1 treatment, and its suppressive effect on CD8+ T cells was also elevated. Depletion of Treg cells in M1-treated groups significantly reinforced antitumor effect of M1. Specific targeting of Treg cells using cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody (Ab) in combination with M1 treatment elicited a more profound tumor suppression and longer overall survival time than M1 alone in both tumor models. Moreover, CTLA-4 Ab further aggrandized antitumor immune response elicited by M1, including increased infiltration of CD45+ immune cells and CD8+ or CD4+ T lymphocytes, decreased ratio of Treg cells to CD4+ T lymphocytes, the intensified lymphocytotoxicity and elevated secretion of cytotoxic cytokines like interferon-γ, granzyme B and perforin. Therefore, our findings constituted a suggestive evidence that targeting Treg cells in M1-based oncolytic virotherapy may achieve a highly response in clinical cancer research.

Visualization of the Oncolytic Alphavirus M1 Life Cycle in Cancer Cells.

Oncolytic alphavirus M1 has been shown to selectively target and kill cancer cells, but cytopathic morphologies induced by M1 virus and the life cycle of the M1 strain in cancer cells remain unclear. Here, we study the key stages of M1 virus infection and replication in the M1 virus-sensitive HepG2 liver cancer cell line by transmission electron microscopy, specifically examining viral entry, assembly, maturation and release. We found that M1 virus induces vacuolization of cancer cells during infection and ultimately nuclear marginalization, a typical indicator of apoptosis. Specifically, our results suggest that the endoplasmic reticulum participates in the assembly of nucleocapsids. In the early and late stage of infection, three kinds of special cytopathic vacuoles are formed and appear to be involved in the replication, maturation and release of the virus. Taken together, our data displayed the process of M1 virus infection of tumor cells and provide the structural basis for the study of M1 virus-host interactions.

Intravenous injection of the oncolytic virus M1 awakens antitumor T cells and overcomes resistance to checkpoint blockade.

Reversing the highly immunosuppressive tumor microenvironment (TME) is essential to achieve long-term efficacy with cancer immunotherapy. Despite the impressive clinical response to checkpoint blockade in multiple types of cancer, only a minority of patients benefit from this approach. Here, we report that the oncolytic virus M1 induces immunogenic tumor cell death and subsequently restores the ability of dendritic cells to prime antitumor T cells. Intravenous injection of M1 disrupts immune tolerance in the privileged TME, reprogramming immune-silent (cold) tumors into immune-inflamed (hot) tumors. M1 elicits potent CD8+ T cell-dependent therapeutic effects and establishes long-term antitumor immune memory in poorly immunogenic tumor models. Pretreatment with M1 sensitizes refractory tumors to subsequent checkpoint blockade by boosting T-cell recruitment and upregulating the expression of PD-L1. These findings reveal the antitumor immunological mechanism of the M1 virus and indicated that oncolytic viruses are ideal cotreatments for checkpoint blockade immunotherapy.

A sensitive pyrimethanil sensor based on porous NiCo2S4/graphitized carbon nanofiber film.

With the extensive use of pesticides, the problem of pesticide residues has become people's concern. In this work, NiCo2S4 nanoneedle arrays grown on an electrospun graphitized carbon nanofiber film (NiCo2S4/GCNF) is successfully prepared by a simple two-step hydrothermal method, and further applied to detection of fungicide pyrimethanil (PMT). NiCo2S4 arrays exhibit a unique core-shell structure with rough surface, providing abundant electrochemically active sites exposed to the electrolyte. The NiCo2S4/GCNF modified electrode displays excellent electrocatalytic activity, and the electrode surface is controlled both by diffusion and adsorption processes. When applied to PMT determination, NiCo2S4/GCNF sensor displays wide linear range from 0.06 to 800 µM with low detection limit (20 nM). Furthermore, the as-proposed sensor also displays other outstanding advantages, including simple preparation, low cost, perfect reproducibility and good application in practical samples. Such attracting analytical properties could be attributed to high electrocatalytic activity of NiCo2S4 and superior electrical conductivity of GCNF frameworks. In addition, the detailed oxidation mechanism of PMT at NiCo2S4/GCNF electrode was also studied. The results indicate that NiCo2S4/GCNF is a promising platform for PMT sensors.

Molecular crystal lithography: a facile and low-cost approach to fabricate nanogap electrodes.

A novel cost-efficient and facile technique, molecular crystal lithography, to fabricate nanogap electrodes efficiently is reported. The gap width of the electrodes can be tuned from ∼9 nm to several micrometers. Organic field-effect transistors based on the nanogap electrodes all exhibit a high performance, indicating the effectiveness and practicability of molecular crystal lithography for mass production of nanogap electrodes.