MSLN

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates. We explored an innovative therapeutic approach by leveraging prognostic oncogenic markers. Instead of inhibiting these marker genes, we harnessed their tumor-modifying potential in the extracellular domain. Surprisingly, many of the proteins highly expressed in PDAC, which is linked to poor survival, exhibited tumor-suppressing qualities in the extracellular environment. For instance, prostate stem cell antigens (PSCA), associated with reduced survival, acted as tumor suppressors when introduced extracellularly...

Since its discovery in 1992, mesothelin (MSLN) has generated significant interest as a therapeutic target. A number of characteristics make it ideal for this purpose. First, it is not expressed on the parenchyma of any vital organs. Second, it is differentially expressed on a number of cancer types that have relatively poor prognosis and lack effective systemic options. Third, it is expressed on the cell membrane making it accessible to large molecule targeted therapies. However, unlike other drug targets that have been exploited for therapeutic benefit, the precise function of MSLN, why it is expressed in certain cancers, and its biological role have not been clearly elucidated...

T cells expressing a mesothelin (MSLN)-specific T cell receptor fusion construct (TRuC® ), called TC-210, have demonstrated robust antitumor activity in preclinical models of mesothelioma, ovarian cancer, and lung cancer. However, they are susceptible to suppression by the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis and lack intrinsic costimulatory signaling elements. To enhance the function of anti-MSLN TRuC-T cells, chimeric switch receptors (CSRs) have been designed to co-opt the immunosuppressive PD-1/PD-L1 axis and to deliver a CD28-mediated costimulatory signal...

No abstract text is available yet for this article.

The design of chimeric antigen receptors (CAR) significantly enhances the antitumor efficacy of T cells. Although some CAR-T products have been approved by FDA in treating hematological tumors, adoptive immune therapy still faces many difficulties and challenges in the treatment of solid tumors. In this study, we reported a new strategy to treat solid tumors using a natural killer-like T (NKT) cell line which showed strong cytotoxicity to lyse 15 cancer cell lines, safe to normal cells and had low or no Graft-versus-host activity...

Mesothelin (MSLN) has been a validated tumor-associated antigen target for several solid tumors for over a decade, making it an attractive option for therapeutic interventions. Novel antibodies with high affinity and better therapeutic properties are needed. In the current study, we have isolated and characterized a novel heavy chain variable (VH) domain 3C9 from a large-size human immunoglobulin VH domain library. 3C9 exhibited high affinity (KD [dissociation constant] <3 nM) and binding specificity in a membrane proteome array (MPA)...

(1) Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. The lack of validated disease biomarkers makes timely diagnosis challenging in most cases. Cell membrane and surface proteins play a crucial role in several routes of oncogenesis. The aim of this study was to evaluate the expression of six membrane antigens on PDAC (CA 19-9, mucin 1 and 4 (MUC1, MUC4), mesothelin (MSLN), Annexin A10 (ANXA10), Glypican-1 (GPC-1)) and their correlation with oncologic outcomes. (2) Methods: Immunohistochemical staining for CA 19...

The long-term efficacy of treatment, heterogeneity, and complexity in the tumor microenvironment remained a clinical challenge in breast cancer (BRCA). There is a need to classify and refine appropriate therapeutic intervention decisions. A stable subtype classification based on gene expression associated with neoadjuvant chemotherapy (NAC) prognosis and assessment on the clinical features, immune infiltration, and mutational characteristics of the different subcategories was performed using ConsensusClusterPlus...

Tbx18 , Wt1 , and Tcf21 have been identified as epicardial markers during the early embryonic stage. However, the gene markers of mature epicardial cells remain unclear. Single-cell transcriptomic analysis was performed with the Seurat, Monocle, and CellphoneDB packages in R software with standard procedures. Spatial transcriptomics was performed on chilled Visium Tissue Optimization Slides (10x Genomics) and Visium Spatial Gene Expression Slides (10x Genomics). Spatial transcriptomics analysis was performed with Space Ranger software and R software...

Chimeric antigen receptor (CAR) T cell therapy has resulted in positive effects on patients with hematologic malignancy but shows limited efficacy in solid tumor treatments due to insufficient trafficking and tumor infiltration, intensive CAR-T-related toxicities, and antigen escape. In this work, we developed and investigated a biodegradable and biocompatible polymeric toroidal-spiral particles (TSPs) as a in vivo cell incubator and delivery device that can be implanted near tumor through a minimally invasive procedure or injected near or into solid tumors by using a biopsy needle...

Paclitaxel (PTX)-based chemotherapy remains the main approach to treating lung cancer but systemic toxicity limits its use. As chimeric antigen receptor-T (CAR-T) cell-derived exosomes contain tumor-targeted CARs and cytotoxic granules (granzyme B and perforin), they are considered potential delivery vehicles for PTX. However, the low drug-loading capacity and hepatotropic properties of exosomes are obstacles to their application to extrahepatic cancer. Here, a hybrid nanovesicle named Lip-CExo@PTX was designed for immunochemotherapy of lung cancer by fusing exosomes derived from bispecific CAR-T cells targeting both mesothelin (MSLN) and programmed death ligand-1 (PD-L1) with lung-targeted liposomes...

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has shown promising results in treating blood cancers, but it has limited efficacy against solid tumors that express mesothelin (MSLN). One of the reasons is the immunosuppressive tumor microenvironment, which consists of physical barriers, multiple mechanisms of immune evasion, and various biochemical factors that favor tumor growth and survival. These factors reduce the antitumor activity of MSLN-targeted CAR T cells in clinical trials...

The emergence of immunotherapy has introduced a promising, novel approach to cancer treatment. While multiple chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable clinical efficacy against leukemia, their effect on solid tumors has been limited. One potential option for treating solid tumors is the engineering of natural killer (NK) cells with CARs. Mesothelin (MSLN), a tumor differentiation antigen, is expressed on triple-negative breast cancer (TNBC) cells, making it a potential target for CAR-NK therapy in the treatment of TNBC...

Intrahepatic mucinous cholangiocarcinoma (IMCC) is a rare subtype of intrahepatic cholangiocarcinoma (IHCC). Limited data describe the genetic characteristics of IMCC and insights on its pathogenesis are lacking. Here, we employed a multi-omics approach to analyze somatic mutations, transcriptome, proteome and metabolome of tumor tissue obtained from a case of IMCC in order to clarify the pathogenesis of IMCC. A total of 54 somatic mutations were detected, including a G12D mutation in KRAS that is likely to be involved in the onset of IMCC...

There has been a concerning increase in the incidence of autoimmune diseases following SARS-CoV-2 infection, with molecular mimicry proposed as a potential mechanism. Our study identified nine fertility-associated proteins (AMH, BMP2, CUBN, DNER, ERCC1, KASH5, MSLN, TPO, and ZP3) that exhibit potential molecular mimicry with MHC-II epitopes of SARS-CoV-2 proteins (N, ORF1A, ORF1AB, and S). We screened for epitopes based on in silico binding using DR-, DQ-, and DP-haplotypes that predispose susceptible individuals to autoimmune diseases...

It is well known that chimeric antigen receptor T-cell immunotherapy (CAR-T-cell immunotherapy) has excellent therapeutic effect in haematological tumours, but it still faces great challenges in solid tumours, including inefficient T-cell tumour infiltration and poor functional persistence. Flap structure-specific endonuclease 1 (FEN1), highly expressed in a variety of cancer cells, plays an important role in both DNA replication and repair. Previous studies have reported that FEN1 inhibition is an effective strategy for cancer treatment...

Mesothelin (MSLN) is an attractive immuno-oncology target, but the development of MSLN-targeting therapies has been impeded by tumor shedding of soluble MSLN (sMSLN), on-target off-tumor activity, and an immunosuppressive tumor microenvironment. We sought to engineer an antibody-based, MSLN-targeted T-cell engager (αMSLN/αCD3) with enhanced ability to discriminate high MSLN-expressing tumors from normal tissue, and activity in the presence of sMSLN. We also studied the in vivo antitumor efficacy of this molecule (NM28-2746) alone and in combination with the multifunctional checkpoint inhibitor/T-cell co-activator NM21-1480 (αPD-L1/α4-1BB)...

OBJECTIVE: The balance between malignant tumor cells and the connective tissue surrounding them determines the aggressiveness of the tumor. We aimed to understand the effects of mesothelin (MSLN) and fibulin1 (FBLN1) expressions on survival in pancreas ductal adenocarcinoma (PDCA), and also whether these proteins have prognostic value for PDCA. METHODS: Of 80 patients in total, 40 who underwent the Whipple procedure for diagnosed PDCA between 2009 and 2016, and 40 patients with diagnosed pancreatitis as the control group, were included in the present study...

INTRODUCTION: Mesothelin (MSLN) is overexpressed in a wide variety of cancers with few therapeutic options and has recently emerged as an attractive target for cancer therapy, with a large number of approaches currently under preclinical and clinical investigation. In this respect, developing mesothelin specific tracers as molecular companion tools for predicting patient eligibility, monitoring then response to mesothelin-targeting therapies, and tracking the evolution of the disease or for real-time visualisation of tumours during surgery is of growing importance...

Anoikis, a form of apoptosis that occurs due to detachment of cells from the extracellular matrix, has been linked to the development of cancer in several studies. However, its role in pancreatic cancer remains incompletely understood. In this study, we utilized univariate Cox regression and LASSO regression analyses to establish a prognostic model for pancreatic adenocarcinoma based on anoikis-related genes in the TCGA database. Additionally, we performed univariate and multifactorial Cox analyses of protein expression results for TCGA pancreatic adenocarcinoma...