Efficacy and advantage of immunotherapy for melanoma via intramuscular co-expression of plasmid-encoded PD-1 and CTLA-4 scFvs.

Immunotherapy, in the shape of immune checkpoint inhibitors (ICIs), has completely changed the treatment of cancer. However, the increasing expense of treatment and the frequency of immune-related side effects, which are frequently associated with combination antibody therapies and Fc fragment of antibody, have limited the patient's ability to benefit from these treatments. Herein, we presented the therapeutic effects of the plasmid-encoded PD-1 and CTLA-4 scFvs (single-chain variable fragment) for melanoma via an optimized intramuscular gene delivery system. After a single injection, the plasmid-encoded ICI scFv in mouse sera continued to be above 150 ng/mL for 3 weeks and reached peak amounts of 600 ng/mL. Intramuscular delivery of plasmid encoding PD-1 and CTLA-4 scFvs significantly changed the tumor microenvironment, delayed tumor growth, and prolonged survival in melanoma-bearing mice. Furthermore, no significant toxicity was observed, suggesting that this approach could improve the biosafety of ICIs combination therapy. Overall, the expression of ICI scFvs in vivo using intramuscular plasmid delivery could potentially develop into a reliable, affordable, and safe immunotherapy technique, expanding the range of antibody-based gene therapy systems that are available.

Characteristics and degradation mechanisms of polychlorinated naphthalenes in surface soil in Yangtze River Delta, China.

Both thermal and environmental processes are significant factors influencing the existing characteristics, e.g., congener distributions, and existing levels, of polychlorinated naphthalenes (PCNs) in the environment. Soil plays an important role in the life cycle of PCNs, but degradation of PCNs in soils has never been reported. In this study, we collected surface soil samples from 13 cities in the Yangtze River Delta, which is one of the most crowded areas of China and analyzed the samples for 75 PCNs. The long-range transportation from polluted areas was the major source for PCNs in remote areas, but the PCN profiles in remote areas reported in our previous studies were different from those in human settlement in this study, indicating there is a transformation of PCNs after emissions from anthropogenic activities. Two experiments were then designed to reveal the degradation mechanisms, including influencing factors, products, and pathways, of PCNs in surface soils. Based on the experiments, we found that the major factor driving the losses of PCNs in surface soils was volatilization, followed by photo irradiation and microbial metabolism. Under photo-irradiation, the PCN structures would be destroyed through a process of dechlorination followed by oxidation. In addition, the dechlorination pathways of PCNs have been established and found to be significantly influenced by the structure-related parameters.

Constructing Built-In Electric Field in NiCo2 O4 -CeO2 Heterostructures to Regulate Li2 O2 Formation Routes at High Current Densities.

Developing catalysts with suitable adsorption energy for oxygen-containing intermediates and elucidating their internal structure-performance relationships are essential for the commercialization of Li-O2 batteries (LOBs), especially under high current densities. Herein, NiCo2 O4 -CeO2 heterostructure with a spontaneous built-in electric field (BIEF) is designed and utilized as a cathode catalyst for LOBs at high current density. The driving mechanism of electron pumping/accumulation at heterointerface is studied via experiments and density functional theory (DFT) calculations, elucidating the growth mechanism of discharge products. The results show that BIEF induced by work function difference optimizes the affinity for LiO2 and promotes the formation of nano-flocculent Li2 O2 , thus improving LOBs performance at high current density. Specifically, NiCo2 O4 -CeO2 cathode exhibits a large discharge capacity (9546 mAh g-1 at 4000 mA g-1 ) and high stability (>430 cycles at 4000 mA g-1 ), which are better than the majority of previously reported metal-based catalysts. This work provides a new method for tuning the nucleation and decomposition of Li2 O2 and inspires the design of ideal catalysts for LOBs to operate at high current density.

Mechanism of transport and toxicity response of Chlorella sorokiniana to polystyrene nanoplastics.

The toxicity of nanoparticles to freshwater microalgae is of significant importance in maintaining the overall stability of aquatic ecosystems. However, the transport mechanism and toxicity response of microalgae towards nanoplastics (NPs) remain to be further investigated. In this study, we examined the toxicity and internalization mechanisms of polystyrene nanoplastics (PS-NPs) in the microalga Chlorella sorokiniana. The results revealed that the PS-NPs inhibited algal cells' growth and disrupted cell integrity upon contact, leading to cell shrinkage or rupture. Moreover, amino-modified PS-NPs (Nano-PS-NH2) exhibited greater toxicity to C. sorokiniana than carboxyl-modified PS-NPs (Nano-PS-COOH). Furthermore, significant inhibition of PS-NPs internalization was observed when four different endocytosis-related inhibitors were used, indicating that internalized PS-NPs can enter algal cells through endocytic pathways. More importantly, C. sorokiniana exposed to Nano-PS-NH2 responded to the reduction in carbon sources and energy resulting from the suppression of photosynthesis by regulating the metabolism of carbohydrates. These findings elucidate the effects of PS-NPs on C. sorokiniana, including their impact on cell morphology and metabolism, while shedding light on the internalization mechanisms of NPs by C. sorokiniana which deepen our understanding of the toxicity of nanoplastics on algae and provide important theoretical support for solving such aquatic ecological environment problems.

Enhancedanti-tumor efficacy through a combination of intramuscularly expressed DNA vaccine and plasmid-encoded PD-1 antibody.

Immune check inhibitors (ICIs) have moderate response rates (~20%-30%) in some malignancies clinically, and, when used in combination with other immunotherapeutic strategies such as DNA tumor vaccines, there is evidence to suggest that they could optimize the efficacy of cancer treatment. In this study, we validated that intramuscular injection of plasmid DNA (pDNA) encoding OVA combined with pDNA encoding α-PD-1 (abbreviated as α-PD-1 in the following treatment groups) may enhance therapeutic efficacy by means of in situ gene delivery and enhanced muscle-specific potent promoter. Mice treated with pDNA-OVA or pDNA-α-PD-1 alone showed weak tumor inhibition in the MC38-OVA-bearing model. In comparison, the combined treatment of pDNA-OVA and pDNA-α-PD-1 resulted in superior tumor growth inhibition and a significantly improved survival rate of over 60% on day 45. In the B16-F10-OVA metastasis model, the addition of the DNA vaccine enhanced resistance to tumor metastasis and increased the populations of CD8+ T cells in blood and spleen. In conclusion, the current research shows that a combination of pDNA-encoded PD-1 antibody and DNA vaccine expressed in vivo is an efficient, safe, and economical strategy for tumor therapy.

Current landscape and future directions of bispecific antibodies in cancer immunotherapy.

Recent advances in cancer immunotherapy using monoclonal antibodies have dramatically revolutionized the therapeutic strategy against advanced malignancies, inspiring the exploration of various types of therapeutic antibodies. Bispecific antibodies (BsAbs) are recombinant molecules containing two different antigens or epitopes identifying binding domains. Bispecific antibody-based tumor immunotherapy has gained broad potential in preclinical and clinical investigations in a variety of tumor types following regulatory approval of newly developed technologies involving bispecific and multispecific antibodies. Meanwhile, a series of challenges such as antibody immunogenicity, tumor heterogeneity, low response rate, treatment resistance, and systemic adverse effects hinder the application of BsAbs. In this review, we provide insights into the various architecture of BsAbs, focus on BsAbs' alternative different mechanisms of action and clinical progression, and discuss relevant approaches to overcome existing challenges in BsAbs clinical application.

Crosstalk Between the Tumor Microenvironment and Cancer Cells: A Promising Predictive Biomarker for Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer treatment and are emerging as promising curative treatments in different type of cancers. However, only a small proportion of patients have benefited from ICIs and there is an urgent need to find robust biomarkers for individualized immunotherapy and to explore the causes of immunotherapy resistance. In this article, we review the roles of immune cells in the tumor microenvironment (TME) and discuss the effects of ICIs on these cell populations. We discuss the potential of the functional interaction between the TME and cancer cells as a predictive biomarker for ICIs. Furthermore, we outline the potential personalized strategies to improve the effectiveness of ICIs with precision.

Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype.

BACKGROUND: Tumor-associated macrophages (TAMs) resemble M2-polarized cells with potent immunosuppressive activity and play a pivotal role in tumor growth and progression. Converting TAMs to proinflammatory M1-like phenotype is thus an attractive strategy for antitumor immunotherapy. METHODS: A mouse IgG1 (kappa) monoclonal Ab, M-860, specific to human lactoferrin (LTF) was generated by using the traditional hybridoma cell fusion technology. TAMs were generated by culturing human and mouse CD14+ monocytes in tumor-conditioned media containing a cytokine cocktail containing recombinant interleukin-4 (IL-4), interleukin-10 (IL-10) and macrophage colony stimulating factor (M-CSF). TAMs after treatment with immunocomplex (IC) between human LTF and M860 (LTF-IC) were phenotypically and functionally characterized by flow cytometry (FACS), ELISA, Q-PCR and killing assays. The antitumor effects of LTF-IC were further analyzed using in vivo experiments employing tumor-bearing human FcγRIIa-transgenic mouse models. RESULTS: Through coligation of membrane-bound CD14 and FcγRIIa, LTF-IC rendered TAMs not only M2 to M1 conversion, evidenced by increased tumor necrosis factor α production, down-regulated M2-specific markers (CD206, arginase-1 and vascular endothelial growth factor) and upregulated M1-specific markers (CD86 and HLA-DR) expression, but also potent tumoricidal activity in vitro. LTF-IC administration conferred antitumor protective efficacy and prolonged animal survival in FcγRIIa-transgenic mice, accompanied by accumulation of M1-like macrophages as well as significantly reduced infiltration of immunosuppressive myeloid-derived suppressor cells and regulatory T cells in solid tumor tissues. CONCLUSIONS: LTF-IC is a promising cancer therapeutic agent capable of converting TAMs into tumoricidal M1-like cells.