PD-L1 restrains PD-1Nrp1 Treg cells to suppress inflammation-driven colorectal tumorigenesis.

T cells function not only as an essential component of host cancer immunosurveillance but also as a regulator of colonic inflammation, a process that promotes colorectal cancer. Programmed death-ligand 1 (PD-L1) is a T cell-negative regulator, but its role in regulation of T cell functions in the context of colorectal cancer is unknown. We report that global deletion of Cd274 results in increased colonic inflammation, PD-1 T cells, and inflammation-driven colorectal tumorigenesis in mice.

In vitro antibody-mediated SARS-CoV-2 infection suppression through human ACE2 receptor blockade.

Vaccines and antibodies that specifically target or neutralize components of the SARS-CoV-2 virus are effective in prevention and treatment of human patients with SARS-CoV-2 infection. However, vaccines and SARS-CoV-2 neutralization antibodies target a subset of epitopes of viral proteins, and the fast evolution of the SARS-CoV-2 virus and the continuing emergence of SARS-CoV-2 variants confer SARS-CoV-2 immune escape from these therapies. ACE2 is the human cell receptor that serves as the entry point for SARS-CoV-2 into human cells and thus is the gatekeeper for SARS-CoV-2 infection of humans.

Verticillins: fungal epipolythiodioxopiperazine alkaloids with chemotherapeutic potential.

Covering: 1970 through June of 2023Verticillins are epipolythiodioxopiperazine (ETP) alkaloids, many of which possess potent, nanomolar-level cytotoxicity against a variety of cancer cell lines. Over the last decade, their activity and mode of action have been explored in detail. Notably, recent studies have indicated that these compounds may be selective inhibitors of histone methyltransferases (HMTases) that alter the epigenome and modify targets that play a crucial role in apoptosis, altering immune cell recognition, and generating reactive oxygen species.

Delivery of Interferon β-Encoding Plasmid via Lipid Nanoparticle Restores Interferon β Expression to Enhance Antitumor Immunity in Colon Cancer.

Type I interferon (IFN-I) plays a critical role in host cancer immunosurveillance, but its expression is often impaired in the tumor microenvironment. We aimed at testing the hypothesis that cationic lipid nanoparticle delivery of interferon β (IFNβ)-encoding plasmid to tumors is effective in restoring IFNβ expression to suppress tumor immune evasion. We determined that IFN-I function in tumor suppression depends on the host immune cells.

The adaptor protein TRAF3 is an immune checkpoint that inhibits myeloid-derived suppressor cell expansion.

Myeloid-derived suppressor cells (MDSCs) are aberrantly expanded in cancer patients and under other pathological conditions. These cells orchestrate the immunosuppressive and inflammatory network to facilitate cancer metastasis and mediate patient resistance to therapies, and thus are recognized as a prime therapeutic target of human cancers. Here we report the identification of the adaptor protein TRAF3 as a novel immune checkpoint that critically restrains MDSC expansion.

Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma.

Unlabelled: High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and nonsterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and nonsterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth.

Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment.

The cellular and molecular mechanisms underlying tumor cell PD-L1 (tPD-L1) function in tumor immune evasion are incompletely understood. We report here that tPD-L1 does not suppress cytotoxic T lymphocyte (CTL) activity in co-cultures of tumor cells and tumor-specific CTLs and exhibits no effect on primary tumor growth. However, deleting tPD-L1 decreases lung metastasis in a CTL-dependent manner in tumor-bearing mice.

5-Fluorouracil Suppresses Colon Tumor through Activating the p53-Fas Pathway to Sensitize Myeloid-Derived Suppressor Cells to FasL Cytotoxic T Lymphocyte Cytotoxicity.

Myelosuppression is a major adverse effect of 5-fluorouracil (5-FU) chemotherapy. However, recent findings indicate that 5-FU selectively suppresses myeloid-derived suppressor cells (MDSCs), to enhance antitumor immunity in tumor-bearing mice. 5-FU-mediated myelosuppression may thus have a beneficial effect for cancer patients.

Radiolabeled Biodistribution of Expansile Nanoparticles: Intraperitoneal Administration Results in Tumor Specific Accumulation.

Nanoparticle biodistribution is an essential component to the success of nanoparticle-based drug delivery systems. Previous studies with fluorescently labeled expansile nanoparticles, or "eNPs", demonstrated a high specificity of eNPs to tumors that is achieved through a materials-based targeting strategy. However, fluorescent labeling techniques are primarily qualitative in nature and the gold-standard for quantitative evaluation of biodistribution is through radiolabeling.

IRF8 Regulates Intrinsic Ferroptosis through Repressing p53 Expression to Maintain Tumor Cell Sensitivity to Cytotoxic T Lymphocytes.

Ferroptosis has emerged as a cytotoxic T lymphocyte (CTL)-induced tumor cell death pathway. The regulation of tumor cell sensitivity to ferroptosis is incompletely understood. Here, we report that interferon regulatory factor 8 (IRF8) functions as a regulator of tumor cell intrinsic ferroptosis.

Upregulation of the EGFR/MEK1/MAPK1/2 signaling axis as a mechanism of resistance to antiestrogen‑induced BimEL dependent apoptosis in ER breast cancer cells.

The epidermal growth factor receptor (EGFR) is commonly upregulated in multiple cancer types, including breast cancer. In the present study, evidence is provided in support of the premise that upregulation of the EGFR/MEK1/MAPK1/2 signaling axis during antiestrogen treatment facilitates the escape of breast cancer cells from BimEL‑dependent apoptosis, conferring resistance to therapy. This conclusion is based on the findings that ectopic BimEL cDNA overexpression and confocal imaging studies confirm the pro‑apoptotic role of BimEL in ERα expressing breast cancer cells and that upregulated EGFR/MEK1/MAPK1/2 signaling blocks BimEL pro‑apoptotic action in an antiestrogen‑resistant breast cancer cell model.

IRF8: Mechanism of Action and Health Implications.

Interferon regulatory factor 8 (IRF8) is a transcription factor of the IRF protein family. IRF8 was originally identified as an essentialfactor for myeloid cell lineage commitment and differentiation. Deletion of leads to massive accumulation of CD11bGr1 immature myeloid cells (IMCs), particularly the CD11bLy6CLy6G polymorphonuclear myeloid-derived suppressor cell-like cells (PMN-MDSCs).

Lipid Nanoparticle Delivery of Fas Plasmid Restores Fas Expression to Suppress Melanoma Growth .

Fas ligand (FasL), expressed on the surface of activated cytotoxic T lymphocytes (CTLs), is the physiological ligand for the cell surface death receptor, Fas. The Fas-FasL engagement initiates diverse signaling pathways, including the extrinsic cell death signaling pathway, which is one of the effector mechanisms that CTLs use to kill tumor cells. Emerging clinical and experimental data indicate that Fas is essential for the efficacy of CAR-T cell immunotherapy.

H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth.

The role of glucose-6-phosphate dehydrogenase (G6PD) in human cancer is incompletely understood. In a metabolite screening, we observed that inhibition of H3K9 methylation suppressed aerobic glycolysis and enhances the PPP in human mesothelioma cells. Genome-wide screening identified G6PD as an H3K9me3 target gene whose expression is correlated with increased tumor cell apoptosis.

Type-2 cGMP-dependent protein kinase suppresses proliferation and carcinogenesis in the colon epithelium.

A large body of evidence has demonstrated that cyclic-guanosine monophosphate (cGMP), signaling has anti-tumor effects that might be used for colon cancer prevention. The tumor-suppressive mechanism and the signaling components downstream of cGMP remain largely unknown. The present study has characterized the expression of cGMP-dependent protein kinases (PKG1, PKG2) in normal and cancerous tissue from human colon.

Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo.

A hallmark of human colorectal cancer is lost expression of FAS, the death receptor for FASL of cytotoxic T lymphocytes (CTLs). However, it is unknown whether restoring FAS expression alone is sufficient to suppress csolorectal-cancer development. The FAS promoter is hypermethylated and inversely correlated with FAS mRNA level in human colorectal carcinomas.

G6PD functions as a metabolic checkpoint to regulate granzyme B expression in tumor-specific cytotoxic T lymphocytes.

Background: Granzyme B is a key effector of cytotoxic T lymphocytes (CTLs), and its expression level positively correlates with the response of patients with mesothelioma to immune checkpoint inhibitor immunotherapy. Whether metabolic pathways regulate expression in CTLs is incompletely understood.

Methods: A tumor-specific CTL and tumor coculture model and a tumor-bearing mouse model were used to determine the role of glucose-6-phosphate dehydrogenase (G6PD) in CTL function and tumor immune evasion.

WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape.

Background: Despite PD-L1 (Programmed death receptor ligand-1) expression on tumor cells and cytotoxic T lymphocytes tumor infiltration in the tumor microenvironment, human pancreatic cancer stands out as one of the human cancers that does not respond to immune checkpoint inhibitor (ICI) immunotherapy. Epigenome dysregulation has emerged as a major mechanism in T cell exhaustion and non-response to ICI immunotherapy, we, therefore, aimed at testing the hypothesis that an epigenetic mechanism compensates PD-L1 function to render pancreatic cancer non-response to ICI immunotherapy.

Methods: Two orthotopic pancreatic tumor mouse models were used for chromatin immunoprecipitation-Seq and RNA-Seq to identify genome-wide dysregulation of H3K4me3 and gene expression.

Pilot-scale production of expansile nanoparticles: Practical methods for clinical scale-up.

One of the foremost challenges in translating nanoparticle technologies to the clinic is the requirement to produce materials on a large-scale. Scaling nanoparticle production methods is often non-trivial, and the success of these endeavors is frequently governed by whether or not an intermediate level of production, i.e.

Expression regulation and function of PD-1 and PD-L1 in T lymphoma cells.

T lymphoma cells may constitutively express PD-1 and PD-L1. The relative role of PD-1 and PD-L1 in T lymphoma is incompletely understood. We report here that PD-1 PDL-1 human T lymphoma cells exhibit constitutive hyperactivation of the TCR signaling and do not respond to PD-L1-mediated suppression in vitro.

Chemoenzymatic modular assembly of O-GalNAc glycans for functional glycomics.

O-GalNAc glycans (or mucin O-glycans) play pivotal roles in diverse biological and pathological processes, including tumor growth and progression. Structurally defined O-GalNAc glycans are essential for functional studies but synthetic challenges and their inherent structural diversity and complexity have limited access to these compounds. Herein, we report an efficient and robust chemoenzymatic modular assembly (CEMA) strategy to construct structurally diverse O-GalNAc glycans.

Psoralen, a natural phytoestrogen, improves diaphyseal fracture healing in ovariectomized mice: A preliminary study.

Psoralen is an effective active component extracted from , which can promote bone formation in osteoporotic animals. However, to the best of our knowledge, its effect on fracture healing has not yet been examined. In the present study, open femur fractures were created in ovariectomy (OVX)-induced osteoporotic mice.

Osteopontin Blockade Immunotherapy Increases Cytotoxic T Lymphocyte Lytic Activity and Suppresses Colon Tumor Progression.

Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action of OPN and determining the efficacy of OPN blockade immunotherapy in suppression of colon cancer.

Streamlined Subclass-Specific Absolute Quantification of Serum IgG Glycopeptides Using Synthetic Isotope-Labeled Standards.

Absolute glycoproteomics quantification has drawn tremendous attention owing to its prospects in biomarker discovery and clinical implementation but is impeded by a general lack of suitable heavy isotope-labeled glycopeptide standards. In this study, we devised a facile chemoenzymatic strategy to synthesize a total of 36 human IgG glycopeptides attached with well-defined glycoforms, including 15 isotope-labeled ones with a mass increment of 6 Da to their native counterparts. Spiking of these standards into human sera enabled simplified, robust, and precise absolute quantification of IgG glycopeptides in a subclass-specific fashion.

Asah2 Represses the p53-Hmox1 Axis to Protect Myeloid-Derived Suppressor Cells from Ferroptosis.

Myeloid-derived suppressor cells (MDSCs) are immune suppressive cells that massively accumulate under pathological conditions to suppress T cell immune response. Dysregulated cell death contributes to MDSC accumulation, but the molecular mechanism underlying this cell death dysregulation is not fully understood. In this study, we report that neutral ceramidase (N-acylsphingosine amidohydrolase [ASAH2]) is highly expressed in tumor-infiltrating MDSCs in colon carcinoma and acts as an MDSC survival factor.