Phagocytosis Of Cells Research Articles

Identification of m6A modification patterns and RBM15 mediated macrophage phagocytosis in pancreatic cancer: An integrative analysis

Pancreatic cancer (PC) responds weakly to conventional immunotherapy. RNA N6-methyladenosine (m6A) modification has an essential role in the immune response, while its potential role in PC tumor microenvironment (TME) immune cell infiltration remains unknown. In this study, we thoroughly assessed the m6A modification patterns of 472 PC samples using 19 m6A regulators, and we systematically correlated these modification patterns with TME immune cell infiltration characteristics. We also created the m6Ascore and evaluated the m6A modification patterns of individual tumors, identified three different m6A modification patterns, and explored the role of the important m6A “writer” RBM15 in the regulation of macrophage function in PC. Two independent PC cohorts confirmed that patients with higher m6Ascore showed significant survival benefit. We verified that knockdown of RBM15 has the ability to inhibit PC growth and to promote macrophage infiltration and enhance phagocytosis of PC cells by macrophages. In conclusion, m6A modifications play a non-negligible role in the formation of TME diversity and complexity in PC. We reveal that inhibition of RBM15 suppresses PC development and modulates macrophage phagocytosis, and provide a more effective immunotherapeutic strategy for PC.

Genetically programmable cell membrane-camouflaged nanoparticles for targeted combination therapy of colorectal cancer

Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens, including prolonged circulation in the bloodstream, specific cell recognition and targeting capabilities, and potential for immunotherapy. Herein, we introduce a cell membrane biomimetic nanodrug platform termed MPB-3BP@CM NPs. Comprising microporous Prussian blue nanoparticles (MPB NPs) serving as both a photothermal sensitizer and carrier for 3-bromopyruvate (3BP), these nanoparticles are cloaked in a genetically programmable cell membrane displaying variants of signal regulatory protein α (SIRPα) with enhanced affinity to CD47. As a result, MPB-3BP@CM NPs inherit the characteristics of the original cell membrane, exhibiting an extended circulation time in the bloodstream and effectively targeting CD47 on the cytomembrane of colorectal cancer (CRC) cells. Notably, blocking CD47 with MPB-3BP@CM NPs enhances the phagocytosis of CRC cells by macrophages. Additionally, 3BP, an inhibitor of hexokinase II (HK2), suppresses glycolysis, leading to a reduction in adenosine triphosphate (ATP) levels and lactate production. Besides, it promotes the polarization of tumor-associated macrophages (TAMs) towards an anti-tumor M1 phenotype. Furthermore, integration with MPB NPs-mediated photothermal therapy (PTT) enhances the therapeutic efficacy against tumors. These advantages make MPB-3BP@CM NPs an attractive platform for the future development of innovative therapeutic approaches for CRC. Concurrently, it introduces a universal approach for engineering disease-tailored cell membranes for tumor therapy.

Exploring the Potential of Plant-Based Nanotechnology in Cancer Immunotherapy: Benefits, Limitations, and Future Perspectives.

Reconceptualizing cancer immunotherapy can be improved if combined with plant production systems and nanotechnology. This review aims to contribute to the knowledge of plant use in nanomedicine and cancer immunotherapy. In the foreground, we outlined each of these approaches; nanomedicine, green synthesis, and immunotherapy. The benefits of plant-based nanoparticles in mending the immune systems were subsequently analyzed, with reference to the literature. The combining effects of biological and therapeutic properties of some phytochemicals and their derivatives, with targeted nanoparticles and selective immunotherapy, can enhance the delivery of drugs and antibodies, and induce antitumor immune responses, via activation of functions of neutrophils, lymphocyte cells, and natural killer cells, and macrophages, resulting in induced apoptosis and phagocytosis of tumor cells, which can improve designing immunotherapeutic strategies targeting cancer, with a larger spectrum compared to the current cytotoxic anticancer drugs commonly used in clinics. This study uncovers the mechanistic drivers of cancer immunoengineering in cancer therapy using plant-based nanomaterials, enhancing therapeutic benefits while minimizing toxic and side effects.

Plasma membrane abundance dictates phagocytic capacity and functional cross-talk in myeloid cells.

Professional phagocytes like neutrophils and macrophages tightly control what they consume, how much they consume, and when they move after cargo uptake. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G protein subunit Gβ4 exhibited profound plasma membrane expansion, accompanied by marked reduction in plasma membrane tension. These biophysical changes promoted the phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. We also found that Gβ4-deficient neutrophils are defective in the normal inhibition of migration following cargo uptake. Sphingolipid synthesis played a central role in these phenotypes by driving plasma membrane accumulation in cells lacking Gβ4. In Gβ4 knockout mice, neutrophils not only exhibited enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. Together, these results reveal an unexpected, biophysical control mechanism central to myeloid functional decision-making.

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCPALL) is a high-risk acute lymphoblastic leukemia subtype characterized by the presence of BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab (RTX), an anti-CD20 monoclonal antibody (mAb) is administered in adult BCP-ALL patients with ≥20% of CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of RTX in combination with TKIs. Consequently, we examined the influence of TKIs on the antitumor effectiveness of anti-CD20 mAbs by evaluating CD20 surface levels and conducting in vitro functional assays. All tested TKIs were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of RTX-mediated complement-dependent cytotoxicity. Interestingly, these TKIs displayed varied effects on NK cell-mediated antibody-dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-mAb-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity within patients' blood, determined by ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKIs for combination therapy with anti-CD20 mAbs.

Effect of SLAMF8 on the phagocytosis of tumor-associated macrophages in colorectal cancer.

e14571 Background: Phagocytosis plays an essential role in innate immunity and is key in bridging innate immunity and adaptive immunity. Phagocytosis checkpoints promote tumor immune escape by inhibiting phagocytosis by tumor-associated macrophages (TAMs). SLAMF8, which is mainly expressed on the surface of TAMs, may be involved in regulating the tumor immune microenvironment. However, its regulation of the phagocytosis of TAMs remains unclear. The present study aims to investigate the effect of SLAMF8 on the phagocytosis of TAMs and to provide a new target for tumor immunotherapy. Methods: The dataset including 458 colorectal cancer (CRC) tissues from the TCGA database was used to analyze the correlation between the expression of SLAMF8 and several classical phagocytosis checkpoint molecules, and the above correlation was further verified by the RNA-sequencing data of 20 CRC tissues in our center. In vitro, the effects of SLAMF8 expression level on tumor cell proliferation and macrophage phagocytosis were also evaluated. RNA sequencing was used to analyze the effect of SLAMF8 on the expression of genes related to promoting macrophage phagocytosis. The effect of SLAMF8 on the expression levels of proteins related to FcR-mediated phagocytosis was detected by flow cytometry. Results: The results from the TCGA dataset and our validation dataset both showed that the SLAMF8 expression was significantly positively correlated with the expression levels of classical phagocytosis checkpoint molecules such as SIGLEC11, SIGLEC10, SIGLEC9, CD274and LILRB1. In vitro, functional tests showed that the phagocytosis of CT26 CRC cells by macrophages was significantly enhanced after SLAMF8 knockdown. RNA sequencing results suggested that the expression levels of molecules related to FcR-mediated phagocytosis were significantly upregulated after the decreased expression of SLAMF8.Flow cytometry analysis confirmed that SLAMF8 inhibited the expression levels of FcR-mediated phagocytosis related proteins such as CD16/32, CD64, and CD11b. Conclusions: SLAMF8 may release the “don’t-eat me” signal to inhibit FcR-mediated phagocytosis of tumor cells by macrophage. Further studies are needed to investigate the underlying mechanism of SLAMF8 on the regulation of macrophage phagocytosis and to test its possibility as a new immunotherapy target.

Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury

We show that redox active iron can induce a regulated form of non-apoptotic cell death and tissue damage called ferroptosis that can contribute to secondary damage and functional loss in the acute and chronic periods after spinal cord injury (SCI) in young, adult, female mice. Phagocytosis of red blood cells at sites of hemorrhage is the main source of iron derived from hemoglobin after SCI. Expression of hemeoxygenase-1 that induces release of iron from heme, is increased in spinal cord macrophages 7 days after injury. While iron is stored safely in ferritin in the injured spinal cord, it can, however, be released by NCOA4-mediated shuttling of ferritin to autophagosomes for degradation (ferritinophagy). This leads to the release of redox active iron that can cause free radical damage. Expression of NCOA4 is increased after SCI, mainly in macrophages. Increase in the ratio of redox active ferrous (Fe2+) to ferric iron (Fe3+) is also detected after SCI by capillary electrophoresis inductively coupled mass spectrometry. These changes are accompanied by other hallmarks of ferroptosis, i.e., deficiency in various elements of the antioxidant glutathione (GSH) pathway. We also detect increases in enzymes that repair membrane lipids (ACSL4 and LPCAT3) and thus promote on-going ferroptosis. These changes are associated with increased levels of 4-hydroxynonenal (4-HNE), a toxic lipid peroxidation product. Mice with mild SCI (30 kdyne force) treated with the ferroptosis inhibitor (UAMC-3203-HCL) either early or delayed times after injury showed improvement in locomotor recovery and secondary damage. Cerebrospinal fluid and serum samples from human SCI cases show evidence of increased iron storage (ferritin), and other iron related molecules, and reduction in GSH. Collectively, these data suggest that ferroptosis contributes to secondary damage after SCI and highlights the possible use of ferroptosis inhibitors to treat SCI.

A first-in-human phase I study of ATG-031, anti-CD24 antibody, in patients with advanced solid tumors or B-cell non-Hodgkin lymphomas (PERFORM).

TPS2691 Background: ATG-031 is a first-in-class humanized cluster of differentiation 24 (CD24) antibody. By disrupting the interaction between CD24, a ‘do not eat me’ signal on cancer cells, and the inhibitory receptor Siglec-10 on tumor-associated macrophages (TAMs), it enhances macrophage-mediated phagocytosis of cancer cells and promotes cytotoxic T cell function in the tumor microenvironment. ATG-031 also triggers antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) towards target tumor cells through its immunoglobulin gamma 1 (IgG1) Fc-dependent effects. Preclinical studies indicated that ATG-031-induced phagocytosis transforms macrophages from a tumor-tolerant M2 phenotype to an antitumor M1 phenotype, significantly inhibiting tumor growth both as monotherapy and synergistically with immune checkpoint inhibitors (ICI) and/or chemotherapies in mouse models. Methods: ATG-031 is undergoing evaluation for safety and preliminary antitumor efficacy in a Phase I, multi-center, open-label clinical study, PERFORM (NCT04986865), in patients with advanced solid tumors or B-cell non-Hodgkin’s lymphoma. The study includes a dose escalation phase and a dose expansion phase. The dose escalation phase enrolls patients with advanced solid tumors (preferred tumor types: lung cancer, breast cancer, ovarian cancer, urothelial cancer, and liver cancer) using a Bayesian Optimal Interval (BOIN) design with 3 to 9 patients at each dose level. A priming dose, defined as an initial lower dose followed by escalation to the full treatment dose, will be applied if Grade ≥2 cytokine release syndrome (CRS) is observed during the dose-limiting toxicity (DLT) period. The dose expansion phase will enroll patients with specific tumor types and will randomize patients into two or more dose levels to determine the recommended Phase II dose (RP2D). The PERFORM study explores an intravenous dose of ATG-031 once every 21 days (1 cycle) to assess DLT during the first two treatment cycles in dose escalation. Key inclusion criteria include histological or cytological confirmation of a solid tumor that has relapsed or has been refractory to standard therapy, at least one measurable lesion per RECIST, and an ECOG performance status of 0 to 1. The study excludes patients with CNS malignancies and those who have experienced Grade ≥3 immune-related adverse events (irAEs) or irAEs leading to prior immunotherapy discontinuation. As of January 2024, 2 sites in the United States have initiated the study, and 4 patients have received ATG-031 treatment at 0.03mg/kg (dose level 1). Clinical trial information: NCT04986865 .

The FIPO23 trial: First-in-human phase I/II study of XON7 in advanced solids tumors.

TPS2673 Background: XON7 is a first-in-class glyco-humanized polyclonal antibody (GH-pAb) targeting selectively multiple tumor-associated antigens. XON7 induces tumor cell apoptosis and promotes the elimination of tumor cells by immune effector cells through CDC (Complement Dependent Cytotoxicity) and ADCP (Antibody-Dependent Cell Phagocytosis). XON7 demonstrated anti-tumor efficacy in mice xenograft models with human solid tumors such as colon, prostate, lung and triple negative breast cancers. Safety pharmacology and toxicology studies in non-human primates demonstrated an acceptable safety profile for XON7. Taken together, these preclinical data support the initiation of human trials in patients with advanced solid tumors. Methods: First-in-patient, multicenter, open-label, two phases (dose-escalation (ESC) followed by dose expansion (EXP)) study of XON7 single agent, in patients with relapsed refractory, locally advanced or metastatic solid tumors without standard available treatments ( NCT06154291). Key eligibility criteria include disease progression after ≤ 4 lines of therapy; age > 18 years; ECOG performance status ≤2; adequate organ functions; no known CNS involvement. All advanced or metastatic tumor types except glioblastoma, can be included during ESC. Primary endpoints: safety, tolerability and determination of MTD/RP2D. Secondary endpoints: pharmacokinetics (PK), pharmacodynamics, immunogenicity and preliminary anti-tumor activity (RECIST 1.1). AEs graded according to CTCAE 5.0. In the ESC part, XON7 is administered as 60-min intravenous infusion every 2 weeks according to an escalating schedule of doses from 1.5 to 20 mg/kg for up to 12, 28-day cycles. Dose escalation/de-escalation is based on the Bayesian Optimal Interval (BOIN) design, up to 45 pts are planned. At the recommended dose, up to 7 EXP cohorts (30 pts each) defined according to the primary tumor site are planned. Bayesian sequential monitoring will be used. Patient recruitment is planned or ongoing at 25 sites worldwide. Results: As of Feb 3rd, 2024, 3 pts are enrolled in the first dose cohort and have received XON7 at dose 1,5 mg/kg Q2W for the first 28-days cycle. Conclusions Accrual is ongoing in this first-in-human trial of XON7. Clinical trial information: NCT06154291 .

Chromosomal instability induced in cancer can enhance macrophage-initiated immune responses that include anti-tumor IgG.

Solid tumors generally exhibit chromosome copy number variation, which is typically caused by chromosomal instability (CIN) in mitosis. The resulting aneuploidy can drive evolution and associates with poor prognosis in various cancer types as well as poor response to T-cell checkpoint blockade in melanoma. Macrophages and the SIRPα-CD47 checkpoint are understudied in such contexts. Here, CIN is induced in poorly immunogenic B16F10 mouse melanoma cells using spindle assembly checkpoint MPS1 inhibitors that generate persistent micronuclei and diverse aneuploidy while skewing macrophages toward a tumoricidal 'M1-like' phenotype based on markers and short-term anti-tumor studies. Mice bearing CIN-afflicted tumors with wild-type CD47 levels succumb similar to controls, but long-term survival is maximized by SIRPα blockade on adoptively transferred myeloid cells plus anti-tumor monoclonal IgG. Such cells are the initiating effector cells, and survivors make de novo anti-cancer IgG that not only promote phagocytosis of CD47-null cells but also suppress tumor growth. CIN does not affect the IgG response, but pairing CIN with maximal macrophage anti-cancer activity increases durable cures that possess a vaccination-like response against recurrence.

Chromosomal instability induced in cancer can enhance macrophage-initiated immune responses that include anti-tumor IgG

Solid tumors generally exhibit chromosome copy number variation, which is typically caused by chromosomal instability (CIN) in mitosis. The resulting aneuploidy can drive evolution and associates with poor prognosis in various cancer types as well as poor response to T-cell checkpoint blockade in melanoma. Macrophages and the SIRPα-CD47 checkpoint are understudied in such contexts. Here, CIN is induced in poorly immunogenic B16F10 mouse melanoma cells using spindle assembly checkpoint MPS1 inhibitors that generate persistent micronuclei and diverse aneuploidy while skewing macrophages toward a tumoricidal ‘M1-like’ phenotype based on markers and short-term anti-tumor studies. Mice bearing CIN-afflicted tumors with wild-type CD47 levels succumb similar to controls, but long-term survival is maximized by SIRPα blockade on adoptively transferred myeloid cells plus anti-tumor monoclonal IgG. Such cells are the initiating effector cells, and survivors make de novo anti-cancer IgG that not only promote phagocytosis of CD47-null cells but also suppress tumor growth. CIN does not affect the IgG response, but pairing CIN with maximal macrophage anti-cancer activity increases durable cures that possess a vaccination-like response against recurrence.

A20 promoted the phagocytosis of lymphoma cells by dendritic cells from activated B-cell-like non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) is a lymphoproliferative disorder derived from either B or T lymphocytes. Among NHL, activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) and T cell non-Hodgkin lymphomas (T-NHL) are poor prognosis and aggressive subtypes. Macrophages are professional phagocytic cells and dendritic cells (DCs) are professional antigen-presenting cells in immune system. Doxorubicin (Dox) and Etoposide (ET) are the most effective anti-cancer drugs. A20 and CYLD are negative regulators of NF-κB-dependent functions in many cell types. Little is known about the roles of A20 and CYLD in regulating functions of DCs and macrophages from NHL. The present study, therefore, explored whether A20/CYLD expression contributes to functions of DCs and macrophages from NHL. To this end, blood samples of seventy-nine patients with ABC DLBCL and T-NHL were examined. Gene expression profile was determined by quantitative RT-PCR and immunophenotype, cell apoptosis and phagocytosis by flow cytometry. As a result, immunophenotypic analysis showed that the numbers of CD13+CD117-, CD56+CD40+ and CD23+CD40+ expressing cells were significantly elevated in ABC DLBCL cases compared to healthy individuals and T-NHL patients. Interestingly, upon treatment of Dox and ET, the phagocytosis of lymphoma cells was significantly reduced by CD11c+CD123- DCs and the percentage of CD56+ mature DCs was significantly enhanced in ABC DLBCL patients only in the presence of A20 siRNA, but not CYLD siRNA. In conclusion, ABC DLBCL patients with low A20 expression were defective in elimination of lymphoma cells by DCs and linked to killer DC expansion in circulation.

#944 Soluble uric acid inhibits neutrophil functions during infections in patients with kidney disease

Abstract Background and Aims Chronic kidney disease (CKD) is one of the most common diseases affecting 8-16% of the world population. Beside cardiovascular complications, infections including sepsis are the second most common cause of death in patients with acute kidney injury (AKI) and CKD. However, the underlying pathomechanisms that contribute to the secondary immunodeficiency related to kidney disease [1] are not well understood. Recent evidence suggests that CKD-related hyperuricemia characterised by elevated serum uric acid (UA) levels suppresses immune cell functions during sterile inflammation [2]. Whether this is also the case during host defense is subject of our current investigation. In this study, we hypothesized that soluble UA inhibits neutrophil effector functions and therefore contributes to the increased infection risk in patients with kidney disease. Method Blood neutrophils were isolated from healthy individuals as well as from patients with kidney diseases, and incubated ex vivo in the presence or absence of 10 mg/dl soluble UA prior to stimulation with bacterial peptides including LPS. Immune cell functions including cytoskeletal changes, immune cell activation, maturation, endo- and phagocytosis (pHrodo Dextran particles, IgG-FITC beads, pHrodo E. coli bioparticles), ROS production, and neutrophil extracellular trap (NET) formation were analysed and quantified using flow cytometry, fluorescence and colorimetric assays, and fluorescence microscopy. In addition, to verify our results we stimulated neutrophils from healthy individuals with sera from hyperuricemic CKD patients. Results Our results show for the first time that soluble UA significantly inhibits the ability of neutrophils to endocytose small particles and phagocytose beads in neutrophils from healthy individuals comparable to the inhibitory effect of Cytochalasin D, an inhibitor of endo- and phagocytosis. Interestingly, unlike neutrophils from AKI patients, neutrophils from CKD patients were significantly less able to phagocytose beads compared to healthy controls with and without stimulation. To mimic the uptake of pathogens more physiologically, pHrodo E. coli bioparticles were used. We found that soluble UA inhibited the phagocytosis of such bioparticles in neutrophils. In addition, our investigation into the formation of ROS showed that soluble UA inhibited specifically nitric oxide, peroxynitrite, hydroxyl radicals and hydrogen peroxide, but to a lower extent the formation of superoxides in neutrophils from healthy individuals, similar to the effectiveness of the radical scavenger N-acetylcysteine. These data were comparable with our cohort study of neutrophils from CKD patients. To examine the mechanism of reduced ROS production, we inhibited NADPH oxidase (DPI) and MPO (4-ABAH) in neutrophils and found that soluble UA has similar inhibitory effects on ROS production like DPI whereas 4-ABAH was more potent. This indicated that soluble UA modulates NADPH oxidase and ROS production, which subsequently resulted in reduced NET formation in neutrophils. Conclusion Our data identify soluble UA as potential immune regulator of the secondary immunodeficiency in patients with kidney disease by inhibiting the endo- and phagocytosis of particles, NADPH-mediated ROS production and NET formation in neutrophils, processes that are important to kill pathogens and fight an infection. Thus, specifically targeting UA with urate-lowering therapy might overcome the suppressed host defence against infection in patients with kidney disease.

Zebularine potentiates anti-tumor immunity by inducing tumor immunogenicity and improving antigen processing through cGAS-STING pathway

DNA methylation is an important epigenetic mechanism involved in the anti-tumor immune response, and DNA methyltransferase inhibitors (DNMTi) have achieved impressive therapeutic outcomes in patients with certain cancer types. However, it is unclear how inhibition of DNA methylation bridges the innate and adaptive immune responses to inhibit tumor growth. Here, we report that DNMTi zebularine reconstructs tumor immunogenicity, in turn promote dendritic cell maturation, antigen-presenting cell activity, tumor cell phagocytosis by APCs, and efficient T cell priming. Further in vivo and in vitro analyses reveal that zebularine stimulates cGAS-STING-NF-κB/IFNβ signaling to enhance tumor cell immunogenicity and upregulate antigen processing and presentation machinery (AgPPM), which promotes effective CD4+ and CD8+ T cell-mediated killing of tumor cells. These findings support the use of combination regimens that include DNMTi and immunotherapy for cancer treatment.

Effect of radiation emitted from mobile phone on innate immunity in mice

This present study aims to explore the potential impact of cell phone radiation on innate immunity in mice. Ninety-six male BALB/C mice aged 2–3 weeks were randomly distributed into 4 groups as blank control, control, TD-SCDMA and LTE-Advanced respectively, with 32 mice in each group. Mice were designed to be exposed to cell phone radiation for 4–8 weeks. Eight mice in each group were taken out for measurement given exposure periods were 4, 6 and 8 weeks respectively. Cell biological technique was conducted to assess the chemotaxis of neutrophils, and a morphological method was performed for the detection of phagocytosis of neutrophil and macrophage, while microbiological means was carried out to test the relative activity of lysozyme in serum of mice. As a result, the chemotaxis ratio of neutrophils was with little statistical difference among the four groups given a shorter exposure period. However, the ratios in TD-SCDMA and LTE-Advanced groups were decreased significantly on the condition that the exposure period was more than 6 weeks. No statistical difference was observed among the four groups during the entire exposure period in terms of the chemotaxis index. Phagocytosis of the innate cells as neutrophil and macrophage showed little change in the two control groups during the whole experimental stages, while the percentage in the two treated groups decreased statistically, and this kind of reduction was prone to feature time dependence. The activities of lysozyme in TD-SCDMA and LTE-Advanced groups declined significantly, further to that, the impact was climbing paralleled with the prolonged duration. It could be deduced that radiation from cell phones could weaken innate immunity in experimental mice; moreover, this adverse effect was seemingly more severe as the radiation exposure continued.

Microplastics dysregulate innate immunity in the SARS-CoV-2 infected lung.

Global microplastic (MP) pollution is now well recognized, with humans and animals consuming and inhaling MPs on a daily basis, with a growing body of concern surrounding the potential impacts on human health. Using a mouse model of mild COVID-19, we describe herein the effects of azide-free 1 μm polystyrene MP beads, co-delivered into lungs with a SARS-CoV-2 omicron BA.5 inoculum. The effect of MPs on the host response to SARS-CoV-2 infection was analysed using histopathology and RNA-Seq at 2 and 6 days post-infection (dpi). Although infection reduced clearance of MPs from the lung, virus titres and viral RNA levels were not significantly affected by MPs, and overt MP-associated clinical or histopathological changes were not observed. However, RNA-Seq of infected lungs revealed that MP exposure suppressed innate immune responses at 2 dpi and increased pro-inflammatory signatures at 6 dpi. The cytokine profile at 6 dpi showed a significant correlation with the 'cytokine release syndrome' signature observed in some COVID-19 patients. The findings are consistent with the recent finding that MPs can inhibit phagocytosis of apoptotic cells via binding of Tim4. They also add to a growing body of literature suggesting that MPs can dysregulate inflammatory processes in specific disease settings.

Cytocompatibility of electrospun poly-L-lactic acid membranes for Bruch's membrane regeneration using human embryonic stem cell-derived retinal pigment epithelial cells.

Cell replacement therapy is under development for dry age-related macular degeneration (AMD). A thin membrane resembling the Bruch's membrane is required to form a cell-on-membrane construct with retinal pigment epithelial (RPE) cells. These cells have been differentiated from human embryonic stem cells (hESCs) in vitro. A carrier membrane is required for cell implantation, which is biocompatible for cell growth and has dimensions and physical properties resembling the Bruch's membrane. Here a nanofiber electrospun poly-L-lactic acid (PLLA) membrane is tested for capacity to support cell growth and maturation. The requirements for laminin coating of the membrane are identified here. A porous electrospun nanofibrous PLLA membrane of ∼50 nm fiber diameter was developed as a prototype support for functional RPE cells grown as a monolayer. The need for laminin coating applied to the membrane following treatment with poly-L-ornithine (PLO), was identified in terms of cell growth and survival. Test membranes were compared in terms of hydrophilicity after laminin coating, mechanical properties of surface roughness and Young's modulus, porosity and ability to promote the attachment and proliferation of hESC-RPE cells in culture for up to 8 weeks. Over this time, RPE cell proliferation, morphology, and marker and gene expression, were monitored. The functional capacity of cell monolayers was identified in terms of transepithelial electrical resistance (TEER), phagocytosis of cells, as well as expression of the cytokines, vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). PLLA polymer fibers are naturally hydrophobic, so their hydrophilicity was improved by pretreatment with PLO for subsequent coating with the bioactive protein laminin. They were then assessed for amount of laminin adsorbed, contact angle and uniformity of coating using scanning electron microscopy (SEM). Pretreatment with 100% PLO gave the best result over 10% PLO treatment or no treatment prior to laminin adsorption with significantly greater surface stiffness and modulus. By 6 weeks after cell plating, the coated membranes could support a mature RPE monolayer showing a dense apical microvillus structure and pigmented 3D polygonal cell morphology. After 8 weeks, PLO (100%)-Lam coated membranes exhibited the highest cell number, cell proliferation, and RPE barrier function measured as TEER. RPE cells showed the higher levels of specific surface marker and gene expression. Microphthalmia-associated transcription factor expression was highly upregulated indicating maturation of cells. Functionality of cells was indicated by expression of VEGF and PEDF genes as well as phagocytic capacity. In conclusion, electrospun PLLA membranes coated with PLO-Lam have the physical and biological properties to support the distribution and migration of hESC-RPE cells throughout the whole structure. They represent a good membrane candidate for preparation of hESC-RPE cells as a monolayer for implantation into the subretinal space of AMD patients.

The Application of 2d Mxene Nanosheet -Based Thermosensitive Gel Delivery System Loaded with Cisplatin and Imiquimod for Lung Cancer.

Lung cancer's high incidence and dismal prognosis with traditional treatments like surgery and radiotherapy necessitate innovative approaches. Despite advancements in nanotherapy, the limitations of single-treatment modalities and significant side effects persist. To tackle lung cancer effectively, we devised a temperature-sensitive hydrogel-based local injection system with near-infrared triggered drug release. Utilizing 2D MXene nanosheets as carriers loaded with R837 and cisplatin (DDP), encapsulated within a temperature-sensitive hydrogel-forming PEG-MXene@DDP@R837@SHDS (MDR@SHDS), we administered in situ injections of MDR@SHDS into tumor tissues combined with photothermal therapy (PTT). The immune adjuvant R837 enhances dendritic cell (DC) maturation and tumor cell phagocytosis, while PTT induces tumor cell apoptosis and necrosis by converting light energy into heat energy. Material characterization employed transmission electron microscopy, X-ray photoelectron spectroscopy, phase transition temperature, and near-infrared thermography. In vitro experiments assessed Lewis cell proliferation and apoptosis using CCK-8, Edu, and TUNEL assays. In vivo experiments on C57 mouse Lewis transplant tumors evaluated the photothermal effect via near-infrared thermography and assessed DC maturation and CD4+/CD8+ T cell ratios using flow cytometry. The in vivo anti-tumor efficacy of MDR@SHDS was confirmed by tumor growth curve recording and HE and TUNEL staining of tumor sections. The hydrogel exhibited excellent temperature sensitivity, controlled release properties, and high biocompatibility. In vitro experiments revealed that MDR@SHDS combined with PTT had a greater inhibitory effect on tumor cell proliferation compared to MDR@SHD alone. Combining local immunotherapy, chemotherapy, and PTT yielded superior anti-tumor effects than individual treatments. MDR@SHDS, with its simplicity, biocompatibility, and enhanced anti-tumor effects in combination with PTT, presents a promising therapeutic approach for lung cancer treatment, offering potential clinical utility.

Characterization of macrophages in head and neck squamous cell carcinoma and development of MRG-based risk signature

Macrophages are immune cells in the TME that can not only inhibit angiogenesis, extracellular matrix remodeling, cancer cell proliferation, and metastasis but also mediate the phagocytosis and killing of cancer cells after activation, making them key targets in anti-tumor immunotherapy. However, there is little research on macrophages and their relation to disease prognosis in HNSCC. Initially, we collected scRNA-seq, bulk RNA-seq, and clinical data. Subsequently, we identified macrophages and distinguished MRGs. Using the K-means algorithm, we performed consensus unsupervised clustering. Next, we used ssGSEA analysis to assess immune cell infiltration in MRG clusters. A risk model was established using multivariate Cox analysis. Then, Kaplan–Meier, ROC curves, univariate and multivariate COX analyses, and C-index was used to validate the predictive power of the signature. The TIDE method was applied to assess the response to immunotherapy in patients diagnosed with HNSCC. In addition, drug susceptibility predictions were made for the GDSC database using the calcPhenotype function. We found that 8 MRGs had prognostic potential. Patients in the MRG group A had a higher probability of survival, and MRG clusters A and B had different characteristics. Cluster A had a higher degree of expression and infiltration in MRG, indicating a closer relationship with MRG. The accuracy of the signature was validated using univariate and multivariate Cox analysis, C-index, and nomogram. Immune landscape analysis found that various immune functions were highly expressed in the low-risk group, indicating an improved response to immunotherapy. Finally, drugs with high sensitivity to HNSCC (such as 5-Fluorouracil, Temozolomide, Carmustine, and EPZ5676) were explored and analyze the malignant characteristics of HNSCC. We constructed a prognostic model using multivariate Cox analysis, consisting of 8 MRGs (TGM2, STC1, SH2D3C, PIK3R3, MAP3K8, ITGA5, ARHGAP4, and AQP1). Patients in the low-risk group may have a higher response to immunotherapy. The more prominent drugs for drug selection are 5-fluorouracil, temozolomide and so on. Malignant features associated with HNSCC include angiogenesis, EMT, and the cell cycle. This study has opened up new prospects for the prognosis, prediction, and clinical treatment strategy of HNSCC.

Targeting tumor‑associated macrophages: Critical players in tumor progression and therapeutic strategies (Review).

Tumor‑associated macrophages (TAMs) are essential components of the tumor microenvironment (TME) and display phenotypic heterogeneity and plasticity associated with the stimulation of bioactive molecules within the TME. TAMs predominantly exhibit tumor‑promoting phenotypes involved in tumor progression, such as tumor angiogenesis, metastasis, immunosuppression and resistance to therapies. In addition, TAMs have the potential to regulate the cytotoxic elimination and phagocytosis of cancer cells and interact with other immune cells to engage in the innate and adaptive immune systems. In this context, targeting TAMs has been a popular area of research in cancer therapy, and a comprehensive understanding of the complex role of TAMs in tumor progression and exploration of macrophage‑based therapeutic approaches are essential for future therapeutics against cancers. The present review provided a comprehensive and updated overview of the function of TAMs in tumor progression, summarized recent advances in TAM‑targeting therapeutic strategies and discussed the obstacles and perspectives of TAM‑targeting therapies for cancers.