Explore the vast range of titles available.

Poor infiltration of activated lymphocytes into tumors represents a fundamental factor limiting the therapeutic effect of adoptive cell immunotherapy. A tumor-penetrating peptide, iRGD, has been widely used to deliver drugs into tumor tissues. In this study, we demonstrate for the first time that iRGD could also facilitate the infiltration of lymphocytes in both 3D tumor spheroids and several xenograft mouse models. In addition, combining iRGD modification with PD-1 knockout lymphocytes reveals a superior anti-tumor efficiency. Mechanistic studies demonstrate that the binding of iRGD to neuropilin-1 results in tyrosine phosphorylation of the endothelial barrier regulator VE-cadherin, which plays a role in the opening of endothelial cell contacts and the promotion of transendothelial lymphocyte migration. In summary, these results demonstrate that iRGD modification could promote tumor-specific lymphocyte infiltration, and thereby overcome the bottleneck associated with adoptive immune cell therapy in solid tumors. The therapeutic efficacy of adoptive T cell transfer is limited by their ability to infiltrate solid tumours. Here, the authors show that loading the tumor penetrating cyclic peptide iRGD on the cell surface of T cells enhances their ability to penetrate the tumour, resulting in enhanced efficacy in a mouse model of gastric cancer.

In situ vaccination is a promising strategy to convert the immunosuppressive tumor microenvironment into an immunostimulatory one with limited systemic exposure and side effect. However, sustained clinical benefits require long-term and multidimensional immune activation including innate and adaptive immunity. Here, we develop a probiotic food-grade Lactococcus lactis -based in situ vaccination (FOLactis) expressing a fusion protein of Fms-like tyrosine kinase 3 ligand and co-stimulator OX40 ligand. Intratumoural delivery of FOLactis contributes to local retention and sustained release of therapeutics to thoroughly modulate key components of the antitumour immune response, such as activation of natural killer cells, cytotoxic T lymphocytes, and conventional-type-1-dendritic cells in the tumors and tumor-draining lymph nodes. In addition, intratumoural administration of FOLactis induces a more robust tumor antigen-specific immune response and superior systemic antitumour efficacy in multiple poorly immune cell-infiltrated and anti-PD1-resistant tumors. Specific depletion of different immune cells reveals that CD8 + T and natural killer cells are crucial to the in situ vaccine-elicited tumor regression. Our results confirm that FOLactis displays an enhanced antitumour immunity and successfully converts the ‘cold’ tumors to ‘hot’ tumors. The probiotic Lactococcus lactis has been used for the delivery of therapeutic molecules. Here the authors engineer Lactococcus lactis to express a fusion protein of Flt3L and OX40 ligand, eliciting anti-tumor immune response in preclinical cancer models.

Cancer vaccines have had some success in the past decade. Based on in-depth analysis of tumor antigen genomics, many therapeutic vaccines have already entered clinical trials for multiple cancers, including melanoma, lung cancer, and head and neck squamous cell carcinoma, which have demonstrated impressive tumor immunogenicity and antitumor activity. Recently, vaccines based on self-assembled nanoparticles are being actively developed as cancer treatment, and their feasibility has been confirmed in both mice and humans. In this review, we summarize recent therapeutic cancer vaccines based on self-assembled nanoparticles. We describe the basic ingredients for self-assembled nanoparticles, and how they enhance vaccine immunogenicity. We also discuss the novel design method for self-assembled nanoparticles that pose as a promising delivery platform for cancer vaccines, and the potential in combination with multiple therapeutic approaches.

Shield tunnel is a type of linear underground structure assembled by lining segments, characterized with long joint, weak stiffness, and strict deformation control requirement. The situation of the long-term deformation and defect of the shield tunnel in soft ground in coastal area of China is severe, mainly attributed to the tunneling-induced ground consolidation, frozen cross passage, groundwater pumping, cyclic train load, and nearby construction. Shield tunnel is buried in ground, and the above factors could result in underlying ground settlement, overlying ground loading/unloading, and at-side ground unloading. As a result, the tunnel could suffer from different types of structural deformation and defect. Based upon the aforementioned different reasons, this study investigates the characteristics of the tunnel deformation and defect corresponding to the different types of ground stress change and deformation. It is found that tunneling-induced ground consolidation, frozen cross passage, groundwater pumping, and cyclic train load mainly contribute to the longitudinal differential settlement but negligible transverse convergence, associated with water leakages at circumferential joints. In comparison, surface surcharge and at-side unloading not only cause significant longitudinal differential deformation but also increase transverse lining internal forces, resulting in water leakages at circumferential joints, longitudinal lining concrete cracks and water leakages. Finally, nearby construction could strongly disturb the ground and cause the generation of excess pore-water pressure, making the shield tunnel deformation develops continuously after the nearby construction is completed.

Objectives GPC3 has been recognized as a promising target for immunotherapy in hepatocellular carcinoma (HCC). However, the GPC3-targeted immunotherapies have shown limited therapeutic efficacy. The use of anti-PD-1/PD-L1 monoclonal antibodies in HCC treatment is considerably constrained. Furthermore, there is still a notable lack of understanding concerning the immune landscape in HCC, especially regarding varied GPC3 expression levels. Therefore, thorough exploration of the intricate tumor immune microenvironment at different GPC3 expression levels is essential for guiding and improving HCC treatment strategies. Methods Sixty patients with HCC were enrolled in this study, receiving a first-line treatment that combined anti-angiogenesis targeted drugs and immunotherapy. Immunohistochemistry was used to assess the levels of GPC3 expression. Multiple immunohistochemical markers, such as CD8, PD-1, LAG3, TIGIT, TIM-3, CD103, Claudin18.2, PD-L1, CD4, Foxp3, CD68, CD163, GPC3, CD11C, CD14, CD66b, and HLA-DR, were used to characterize the immune microenvironment and spatial distribution of immune cells in HCC tumors with different levels of GPC3 expression. Cell expression levels and spatial distribution were determined by fluorescence staining and subsequent analysis of fluorescence intensity using the Panoramic Pathology Workstation (Pano ATLAS). This approach facilitated a detailed examination of cell characteristics and spatial information within the samples. Results Based on the result of GPC3 immunohistochemical analysis, patients with strong positive GPC3 expression were classified as high GPC3 expression, while the others were classified as low GPC3 expression. Patients in the low GPC3 expression group had longer overall survival (OS) than in the high group ( P  = 0.003, HR = 2.9240). Further exploration of the immune microenvironment based on different GPC3 expression levels revealed that in high GPC3 expression group, the proportions of CD8 + T cells( P  = 0.0435), TIM-3 + T cells( P  = 0.0447), CD103 + CD8 + tissue-resident T cells( P  = 0.0410), CD11C + CD14 − DC cells( P  = 0.0497), CD11C + HLA-DR − DC cells( P  = 0.0309), CD11C + CD14 − HLA-DR − DC cells( P  = 0.0233), and CD11C + CD14 − CD66b − DC cells( P  = 0.0474) were all higher compared to low expression group. At spatial distances of 10 μm, 20 μm, and 30 μm, the levels of CD8 + T cells were higher in the high expression group compared to the low expression group (high vs. low: P  = 0.0281, P  = 0.0236, P  = 0.0220). Conclusions Multiple immunohistochemistry is a powerful technique for exploring the intricate immune microenvironment of hepatocellular carcinoma, enabling the precise identification of diverse cell subsets and their spatial distribution within the tumor microenvironment. This methodology provides valuable insights into the complex interactions and spatial organization of immune cells in the context of hepatocellular carcinoma progression. Low GPC3 expression in HCC patients indicates potential benefits from combined targeted and immunotherapy. Different levels of GPC3 expression levels can predict the effectiveness of targeted combination immunotherapy in HCC patients. Additionally, different GPC3 expression patterns in HCC patients correspond to unique tumor immune microenvironments, which have implications for guiding HCC treatment approaches.

Background: Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease with a complex etiology, creating a significant unmet clinical need for safer and more effective therapeutics. Coix seed oil (CSO), a traditional Chinese medicine with a long history of use against RA, represents a promising candidate; however, its precise mechanisms of action remain largely unexplored. Objectives: This study aimed to elucidate the mechanistic basis for the anti-arthritic effects of CSO, with a specific focus on its role in modulating the gut-joint axis. Methods: A collagen-induced arthritis (CIA) rat model was employed. The therapeutic efficacy of CSO was evaluated through detailed assessments of arthritic symptoms, joint histopathology, and Micro-CT analysis. To unravel the mechanism, an integrative multi-omics approach was applied, combining untargeted fecal metabolomics with targeted serum metabolomics, which pinpointed butyric acid as a key differential metabolite. This was integrated with 16S rRNA sequencing to profile gut microbiota remodeling. The causal role of butyrate was further verified by exogenous sodium butyrate supplementation in CIA mice. Finally, network pharmacology predictions of potential effector proteins were experimentally validated in vivo using immunofluorescence and qPCR. Results: CSO treatment significantly alleviated joint swelling and bone damage in CIA rats after the treatment of 7 days, especially on day 35. CSO primarily restored gut dysbiosis in the CIA model by upregulating butyrate levels, increasing four butyrate-producing probiotics at the genus level, and reducing two pathogenic bacteria. Further exogenous butyrate supplementation validated its ability to improve RA phenotypes. Network pharmacology analysis speculated that there were 142 common targets between CSO and RA, among which NLRP3 was its potential effector protein. In vivo studies verified the suppression of NLRP3 inflammasome activation and reduced expression of subsequent inflammatory mediators by CSO. Conclusions: Coix Seed Oil alleviates RA by orchestrating a dual-mechanism action, it remodels the gut microbiota to enhance the production of the microbiotic metabolite butyrate, while also inhibiting the NLRP3 inflammasome pathway. These findings collectively elucidate that CSO mediates its anti-arthritic effects through a novel “gut-butyrate-joint” axis, underscoring its potential as a promising dietary supplement or therapeutic agent derived from medicine-food homology for the management of RA.

Background Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by symmetric arthritis. Coix Seed Oil (CSO) has been shown to reduce inflammation in collagen induced arthritis (CIA) rats. However, the effect of CSO on synovial angiogenesis in RA is unknown. In this study, we aimed to explore whether CSO could inhibit RA synovial angiogenesis and elucidate the underlying mechanisms. Methods CIA rat models were established and subjected to different doses of CSO treatments for four weeks in vivo. Arthritis index, paw swelling, and weight were recorded to assess clinical symptoms. Hematoxylin and Eosin staining, Safarnin O fast green staining, Micro-CT, Immunohistochemical, and Immunofluorescence (IF) staining were performed to examined changes in synovial and joint tissues. The serum HIF-1α and VEGF-A levels were evaluated through enzyme-linked immunosorbent assay. Fibroblast-like synoviocytes (FLS) of rats was stimulated with tumor necrosis factor-α (TNF-α) for developing inflammatory model in vitro. Optimal concentrations of CSO and TNF-α for stimulation were measured through Cell Counting Kit-8 test. Wound healing and Transwell migration experiments were employed to determine FLS migratory ability. IF staining was performed to assess HIF-1α nuclear translocation in FLS. Protein levels of SIRT1, HIF-1α, VEGF-A, and CD31 were assessed through Western blot. The isolated aortic rings were induced with recombinant rat VEGF-A 165 (VEGF-A 165 ) to observe the CSO inhibitory impact on angiogenesis ex vivo. Results CSO attenuated the progression of arthritis in CIA rats, mitigated histopathological deterioration in synovial and joint tissues, significantly inhibited immature vessels labeled with CD31 + /αSMA − , and reduced the micro-vessels in VEGF-A 165 induced aortic rings. Moreover, it upregulated SIRT1 protein levels in CIA rats and TNF-α induced FLS, but decreased HIF-1α and VEGF-A protein levels. Furthermore, CSO inhibited the migration ability and HIF-1α nuclear translocation of TNF-α induced FLS. Finally, suppressing SIRT1 levels in TNF-α induced FLS enhanced their migration ability, HIF-1α nuclear translocation, and the protein levels of HIF-1α, VEGF-A, and CD31, whereas the inhibitory effect of CSO on TNF-α induced FLS was severely constrained. Conclusions This study indicates that CSO can alleviate synovial angiogenesis through suppressing HIF-1α/VEGF-A signaling pathways via SIRT1 in CIA rats.

There is currently much interest in cancer cell targeting and tumor penetrating for research and therapeutic purposes. To improve targeting delivery of antitumor drugs to gastric cancer, in this study, a tumor-targeting biocompatible drug delivery system derived from erythrocyte membrane for delivering paclitaxel (PTX) was constructed. Erythrocyte membrane of human red blood cells (RBCs) were used for preparing of erythrocyte membrane-derived vesicles. 1,2-distearoyl- -glycero-3-phosphoethanolamine- -(maleimide[polyethylene glycol]-3400) (DSPE-PEG-MAL), a phospholipid derivative, was used to insert tumor-targeting molecular into erythrocyte membrane-derived vesicles. A lipid insertion method was used to functionalize these vesicles without the need for direct chemical conjugation. Furthermore, a tumor-penetrating bispecific recombinant protein named anti-EGFR-iRGD was used for the first time in this work to enable nanosystem to target and penetrate efficiently into the tumor site. Paclitaxel (PTX)-loaded anti-EGFR-iRGD-modified erythrocyte membrane nano-system (anti-EGFR-iRGD-RBCm-PTX, abbreviated to PRP) were manufactured. PRP was spheroid, uniformly size, about 171.7±4.7 nm in average, could be stable in vitro for 8 days, and released PTX in a biphasic pattern. PRP showed comparable cytotoxicity toward human gastric cancer cells in vitro. In vivo studies showed that, PRP accumulated in tumor site within 2 h of administration, lasted longer than 48 h, and the tumor volume was reduced 61% by PRP treatment in Balb/c nude mice, without causing severe side effects. PRP has potential applications in cancer treatment and as an adjunct for other anticancer strategies.

Background Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in the treatment of hematologic malignancies, while the success has not yet been replicated in solid tumors. To some extent, the disappointing results can be attributed to the paucity and heterogeneity of target antigens in solid tumors since adequate antigens are the cornerstone for CAR-T cells to recognize and attack tumor cells. Methods We established a target-redirected universal CAR-T (TRUE CAR-T) cell therapeutic modality, in which exogenous antigens are loaded onto fusogenic nanoparticles to achieve in situ modification of cell membrane in solid tumors, providing targets for subsequent CAR-T cell therapy. The modification effect was evaluated by flow cytometry and confocal microscopic imaging. The in vivo metabolism and biodistribution of fusogenic antigen loaded nanoparticles (F-AgNPs) was explored using near infrared living imaging. Then F-AgNPs mediated in situ antigen modification were cooperated with corresponding CAR-T cell therapy, and its antitumor efficacy was evaluated using immune function experiments and further investigated in different tumor models. Results Using F-AgNPs, exogenous antigens were selectively modified onto tumor cell membranes through membrane fusion, spread deeper into tumor tissues through intercellular lipid transfer, further activating corresponding CAR-T cells and mediating antitumor immune responses towards multiple types of tumor cells, despite of their inherent antigen profiles. The cooperative treatment of F-AgNPs and CAR-T cell therapy successfully suppressed tumor proliferation and prolonged survival in both subcutaneous and peritoneally disseminated tumor models. Conclusion The fusogenic nanoparticle-based in situ antigen modification overcome the limitation of target antigens paucity and heterogeneity in solid tumors, improving the efficacy and broadening the applications of CAR-T cells, thus establishing a novel TRUE CAR-T cell therapeutic modality with universal application and translational potential in immunotherapies for solid tumors.

Resistance to irradiation (IR) remains a major therapeutic challenge in tumor radiotherapy. The development of novel tumor‐specific radiosensitizers is crucial for effective radiotherapy against solid tumors. Here, we revealed that remodeling tumor tissue penetration via tumor‐penetrating peptide internalizing arginine–glycine–aspartic acid RGD (iRGD) enhanced irradiation efficacy. The growth of 4T1 and CT26 multicellular tumor spheroids (MCTS) and tumors was delayed significantly by the treatment with IR and iRGD. Mechanistically, iRGD reduced hypoxia in MCTS and tumors, resulting in enhanced apoptosis after MCTS and tumors were treated with IR and iRGD. This is the first report that shows enhanced radiation efficacy by remodeling tumor‐specific tissue penetration with iRGD, implying the potential clinical application of peptides in future tumor therapy. The development of novel tumor‐specific radiosensitizers is crucial for effective radiotherapy against solid tumors. Here, we revealed that remodeling tumor tissue penetration via tumor‐penetrating peptide internalizing RGD (iRGD) enhanced irradiation efficacy through reducing tumor hypoxia. This is the first report that shows enhanced radiation efficacy by remodeling tumor‐specific tissue penetration with iRGD, implying the potential clinical application of peptides in future tumor therapy.