Claudin-1 Research Articles

Reduction of Chemoresistance by Claudin-14-Targeting Peptide in Human Colorectal Cancer Cells.

The expression of claudins (CLDNs), major components of tight junctions (TJs), is abnormal in various solid tumors. CLDN14 is highly expressed in human colorectal cancer (CRC) tissues and confers chemoresistance. CLDN14 may become a novel therapeutic target for CRC, but CLDN14-targeting drugs have not been developed. Here, we searched for a CLDN14-targeting peptide, which can suppress CLDN14 expression and chemoresistance using human CRC-derived DLD-1 and LoVo cells. Among some short peptides which mimic the second extracellular loop structure of CLDN14, PSGMK most strongly suppressed the protein expression of CLDN14. The mRNA expression of other endogenous TJ components was unchanged by PSGMK. The PSGMK-induced reduction of CLDN14 protein was inhibited by chloroquine, a lysosome inhibitor, and monodansylcadaverine, a clathrin-dependent endocytosis inhibitor, indicating that PSGMK may enhance endocytosis and lysosomal degradation of CLDN14. In a three-dimensional culture model, the oxidative stress was significantly reduced by PSGMK, whereas hypoxia stress was not. Furthermore, the expression levels of nuclear factor erythroid 2-related factor 2, an oxidative stress response factor, and its target genes were decreased by PSGMK. These results suggest that PSGMK relieves stress conditions in spheroids. The cell viability of spheroids was decreased by anticancer drugs such as doxorubicin and oxaliplatin, which was exaggerated by the cotreatment with PSGMK. Our data indicate that CLDN14-targeting peptide, PSGMK has an anti-chemoresistance effect in CRC cells.

Inflammation-Induced Claudin-2 Upregulation Limits Pancreatitis Progression by Enhancing Tight Junction-Controlled Pancreatic Ductal Transport.

Pancreatitis is an inflammatory disease of the pancreas that can arise due to various factors, including environmental risks such as diet, alcohol, and smoking, as well as genetic predispositions. In some cases, pancreatitis may progress and become chronic, leading to irreversible damage and impaired pancreatic function. Genome-wide association studies (GWAS) have identified polymorphisms at the X-linked CLDN2 locus as risk factors for both sporadic and alcohol-related chronic pancreatitis. CLDN2 encodes claudin-2 (CLDN2), a paracellular cation-selective channel localized at tight junctions and expressed in the pancreas and other secretory organs. However, whether and how CLDN2 may modify pancreatitis susceptibility remains poorly understood. We aimed to clarify the potential role of CLDN2 in the onset and progression of pancreatitis. We employed multiple methodologies to examine the role of CLDN2 in human pancreatic tissue, caerulein-induced experimental pancreatitis mouse model, and pancreatic ductal epithelial organoids. In both human chronic pancreatitis tissues and caerulein-induced experimental pancreatitis, CLDN2 protein was significantly upregulated in pancreatic ductal epithelial cells. Our studies using pancreatic ductal epithelial organoids and mice demonstrated the inflammatory cytokine IFNγ upregulates claudin-2 expression at both RNA and protein levels. Following caerulein treatment, Ifng KO mice had diminished upregulation of CLDN2 relative to WT mice, indicating that caerulein-induced claudin-2 expression is partially driven by IFNγ. Functionally, Cldn2 knockout mice developed more severe caerulein-induced experimental pancreatitis, indicating CLDN2 plays a protective role in pancreatitis development. Pancreatic ductal epithelial organoid-based studies demonstrated that CLDN2 is critical for sodium-dependent water transport and necessary for cAMP-driven, CFTR-dependent fluid secretion. These findings suggest that functional crosstalk between CLDN2 and CFTR is essential for fluid transport in pancreatic ductal epithelium, which may protect against pancreatitis by adjusting pancreatic ductal secretion to prevent worsening autodigestion and inflammation. In conclusion, our studies suggest CLDN2 upregulation during pancreatitis may play a protective role in limiting disease development, and decreased CLDN2 function may increase pancreatitis severity. These results point to the possibility of modulating pancreatic ductal CLDN2 function as an approach for therapeutic intervention of pancreatitis.

Positive effect of fermented sorghum on productivity, jejunal histomorphology, and tight junction gene expression in broiler chickens

This study aimed to investigate the effects of dietary fermented sorghum (FS) as a substitute for corn on growth performance, jejunal histomorphology, cecal short-chain fatty acid (SCFA) levels, and gene expression of tight junctions in broiler chickens. A total of 240 one-day-old male New Lohmann Indian River chicks were randomly divided into five groups, with each group receiving different dietary treatments: a control group (CTRL) with a basal diet, groups supplemented with 10% (NFS10) and 20% (NFS20) non-fermented sorghum, and groups supplemented with 10% (FS10) and 20% (FS20) fermented sorghum. Each group was further divided into six replications, with eight birds per replicate. Orthogonal contrasts were used to compare the feed treatments (fermented sorghum and non-fermented sorghum) to the control. The results revealed that the inclusion of 20% fermented sorghum significantly increased feed intake (FI, P = 0.005), body weight (BW; P = 0.025), and body weight gain (BWG; P = 0.010) compared to other groups. Additionally, the FS20 group exhibited a notable increase in villus height (P = 0.001). There were significant differences in cecal short-chain fatty acid (SCFA) production among the treatment groups (P < 0.05). Furthermore, fermented sorghum notably upregulated the gene expression of occludin (OCLN, P = 0.008), without significant impacts on the expression of claudin-1 (CLDN-1), junctional adhesion molecules-2 (JAM-2), and zonula occludens-1 (ZO-1). In conclusion, addition of 20% fermented sorghum in broiler diets could enhance growth performance and intestinal histomorphology, indicating its potential as a beneficial feed ingredient for poultry production.

Comparative evaluation of the modulatory role of 1,25-dihydroxy-vitamin D3 on endoplasmic reticulum stress-induced effects in 2D and 3D cultures of the intestinal porcine epithelial cell line IPEC-J2

BackgroundThe use of conventional two-dimensional (2D) culture of the porcine intestinal epithelial cell (IEC) line IPEC-J2 in animal nutrition research has the disadvantage that IEC function is studied under unphysiological conditions, which limits the ability of transferring knowledge to the in vivo-situation. Thus, the aim of the present study was to establish a more convincing and meaningful three-dimensional (3D) culture of IPEC-J2 cells, which allows to study cell function in a more tissue-like environment, and to compare the effect of the endoplasmic reticulum (ER) stress inducer tunicamycin (TM) on ER stress indicators and the expression of tight junction proteins (TJP), inflammatory and apoptosis-related genes and the modulatory role of 1,25-dihydroxy-vitamin D3 (1,25D3) on these parameters in 2D and 3D cultures of IPEC-J2 cells.ResultsA published protocol for 3D culture of Caco-2 cells was successfully adopted to IPEC-J2 cells as evident from fully differentiated 3D IPEC-J2 spheroids showing the characteristic spherical architecture with a single layer of IPEC-J2 cells surrounding a central lumen. Treatment of 2D IPEC-J2 cells and 3D IPEC-J2 spheroids with TM for 24 h markedly increased mRNA and/or protein levels of the ER stress target genes, heat shock protein family A (Hsp70) member 5 (HSPA5) and DNA damage inducible transcript 3 (DDIT3), whereas co-treatment with TM and 1,25D3 did not mitigate TM-induced ER stress in IPEC-J2 cells in the 2D and the 3D cell culture. In contrast, TM-induced expression of pro-inflammatory [interleukin-6 (IL6), IL8] and pro-apoptotic genes [BCL2 associated X, apoptosis regulator (BAX), caspase 3 (CASP3), CASP8] and genes encoding TJP [TJP1, claudin 1 (CLDN1), CLDN3, occludin (OCLN), cadherin 1 (CDH1), junctional adhesion molecule 1 (JAM1)] was reduced by co-treatment with TM and 1,25D3 in 3D IPEC-J2 spheroids but not in the 2D cell culture.ConclusionsThe effect of 1,25D3 in the IPEC-J2 cell culture is dependent on the culture model applied. While 1,25D3 does not inhibit TM-induced expression of genes involved in inflammation, apoptosis and TJP in conventional 2D cultures of IPEC-J2 cells, TM-induced expression of these genes is abrogated by 1,25D3 in the more meaningful 3D IPEC-J2 cell culture model.

PPM1G Inhibits Epithelial-Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter.

Ten-eleven translocation protein 1 (TET1) functions as an epigenetic regulatory molecule, mediating the majority of DNA demethylation, and plays a role in the development of different types of cancers by regulating the expression of proto-oncogenes and oncogenes. Here it is found that TET1 is highly expressed in cholangiocarcinoma (CCA) and is associated with a poor prognosis. In addition, TET1 promotes claudin-3 (CLDN3) transcription by targeting the CLDN3 promoter region between -16 and 512 for demethylation. PPM1G functions as a protein dephosphorylase, catalyzing the dephosphorylation of TET1. This results in the destabilization of the TET1 protein, thereby impairing the targeting of the CLDN3 promoter for demethylation. Two phosphatase inhibitors, staurosporine and AZD0156, inhibit epithelial-to-mesenchymal transition (EMT) in cholangiocarcinoma cells by suppressing TET1 expression. In conclusion, it is also demonstrated that PPM1G can be employed as a therapeutic target to impede the progression of CCA by catalyzing the dephosphorylation of TET1, which diminishes the capacity of TET1 to target the CLDN3 promoter to activate transcription and inhibit EMT in CCA.

Antibody-drug conjugates as targeted therapy for treating gynecologic cancers: update 2025.

Provide the most up-to-date information on the dynamic landscape of antibody-drug conjugates (ADCs) in gynecologic cancers. We discuss the latest research that supports the approved ADCs and outline the ongoing trials and preliminary results that may lead to ADC approvals in the future. Current gaps in knowledge and areas for future research are discussed. ADCs are rapidly changing the landscape of gynecologic cancer care. Three ADCs are currently FDA approved and used routinely in clinical practice, with many more currently in clinical development. The most common ADC target is folate receptor alpha of which there are 8 different folate receptor targeting ADCs in development. Other targets under investigation include trophoblast cell surface antigen-2 (Trop-2), claudin-6 (CLDN6), cadherin-6 (CDH6), nectin-4, HER-2 and B7-H4. ADCs can cause new and unique adverse effects, including ocular toxicities and interstitial lung disease. ADCs offer the opportunity for a more effective and personalized treatment approach for gynecologic cancer patients. Side effects must be closely monitored, and preventive measures must be followed to maximize benefit and minimize toxicity. A better understanding of the role of target proteins as biomarkers to predict response to ADCs will be critical for successful clinical implementation of ADCs and further research in this area is necessary.

Effects of hyperglycemia on airway epithelial barrier function in WT and CF 16HBE cells

Cystic fibrosis related diabetes (CFRD), the main co-morbidity in cystic fibrosis (CF), is associated with higher rates of lung function decline. We hypothesize that airway epithelial barrier function is impaired in CF and is further exacerbated under hyperglycemia, worsening pulmonary outcomes. Using 16HBE cells, we studied the effects of hyperglycemia in airway epithelial barrier function. Results show increased paracellular dye flux in CF cells in response to insulin under hyperglycemia. Gene expression experiments identified claudin-4 (CLDN4) as a key tight junction protein dysregulated in CF cells. CLDN4 protein localization by confocal microscopy showed that CLDN4 was tightly localized at tight junctions in WT cells, which did not change under hyperglycemia. ln contrast, CLDN4 was less well-localized in CF cells at normal glucose and localization was worsened under hyperglycemia. Treatment with highly effective modulator compounds (ETI) reversed this trend, and CFTR rescue was not affected by insulin or hyperglycemia. Bulk RNA sequencing showed differences in transcriptional responses in CF compared to WT cells under normal or high glucose, highlighting promising targets for future investigation. One of these targets is protein tyrosine phosphatase receptor type G (PTPRG), which has been previously found to play a role in defective Akt signaling and insulin resistance.

CLDN11 deficiency upregulates FOXM1 to facilitate breast tumor progression through hedgehog signaling pathway

Claudins (CLDNs) play a crucial role in regulating the permeability of epithelial barriers and can impact tumor behavior through alterations in their expression. However, the precise mechanisms underlying the involvement of CLDNs in breast cancer progression remain unclear. This study aimed to investigate the role of CLDN11 in breast cancer progression. Utilizing the TCGA database and clinical specimens from breast cancer patients, we observed reduced expression of CLDN11 in tumor tissues, which correlated with poor prognosis in breast cancer patients. In vitro, silencing of CLDN11 enhanced the proliferative and migratory characteristics of breast cancer cell lines MCF-7 and MDA-MB-231. Mechanistically, CLDN11 deficiency promoted the upregulation of Forkhead Box M1 (FOXM1) by activating the hedgehog signaling pathway, thereby sustaining tumor progression in breast cancer. In vivo, blockade of hedgehog signaling suppressed the tumor progression induced by CLDN11 silencing. Our study highlights the significance of the CLDN11/FOXM1 axis in breast cancer progression, suggesting CLDN11 as a potential diagnostic indicator and therapeutic target for clinical therapy.

Experimental colitis is comorbid with social interaction deficits and anxiety-like behaviors in mice: mechanistic intuitions into neuroinflammation and Claudin 5 expression in the hippocampus.

Inflammatory bowel disease (IBD) is accompanied by psychiatric disorders, including Schizophrenic-like manifestations. Although incompletely illustrated, intestinal mucosal membrane damage and blood-brain barrier (BBB) penetrability may have significant roles in psychiatric symptoms of IBD. This study aimed to investigate role of the Claudin-5 (CLDN5) (a regulator of the permeability of BBB) and neuroinflammatory response in the comorbid behavioral disorders in experimental colitis in mice. Acetic acid was used to induce colitis in mice. 7 days after induction of colitis, behaviors including social interaction and locomotor activity as well as anxiety-like behaviors were evaluated. Then, the colon was extracted for gross and microscopic evaluations. The expression of CLDN5, TNF-α, IL1β and IL23 was measured by RT-PCR in the colon and hippocampus. Histopathologic evaluations demonstrated mucosal, submucosal, and crypt-related damages in the colon. The negative and positive number of social interactions significantly increased in the colitis group. A considerable increase in locomotor activities (horizontal and vertical components) shown in the colitis group. Mice in colitis group spent less time in the central zone in the open field apparatus. Gene expressions of TNF-α, IL1β, and IL23 increased and CLDN5 decreased in the colitis group. The barrier function of the intestine and brain would be impaired, partially at least, following colitis (as we observed decrease in CLDN5 gene expression). Furthermore, we found that beside inflammatory response in the colon, a neuro-immune response triggered in the hippocampus following colitis. These alterations probably, mediated comorbid behavioral disorders in acetic acid-induced colitis in mice.

Micro RNA-175 Targets Claudin-1 to Inhibit Madin–Darby Canine Kidney Cell Adhesion

Background: The Madin–Darby canine kidney (MDCK) cell line constitutes a key component of influenza vaccine production, but its dependence on adherent growth limits cell culture density and hinders vaccine yield. There is evidence that the use of gene editing techniques to inhibit cell adhesion and establish an easily suspended cell line can improve vaccine yield; however, the mechanisms underlying MDCK cell adhesion are unclear. Methods: In this study, we used transcriptomics to analyse differentially expressed mRNAs and miRNAs in adherent and suspension cultures of MDCK cells. Results: We found that claudin-1 (CLDN1) expression was downregulated in the suspension MDCK cells and that CLDN1 promotes MDCK cell–extracellular matrix adhesion. Additionally, microRNA (miR)-175 expression was upregulated in the suspension MDCK cells. Importantly, we demonstrated that miR-175 inhibits MDCK cell adhesion by targeting the CLDN1 3′-untranslated region (UTR). These findings contribute to a more comprehensive understanding of the regulatory mechanisms modulating cell adhesion and provide a basis for establishing suspension-adapted, genetically engineered cell lines. Our work could also facilitate the identification of targets for tumour therapy.

Capsaicin attenuates the effect of inflammatory cytokines in a HaCaT cell model for basal keratinocytes.

The resolution of the skin's inflammatory response is only possible if its barrier function is restored. TRPV1 channel activation plays an important role during inflammation but the effect of this activation on the skin barrier under inflammatory conditions has not been clarified. We hypothesize that it could potentially aid the keratinocyte barrier by reducing inflammatory cytokine release and promoting tight junction development. To explore the role of TRPV1 activation in inflammation, we designed and optimized an in vitro model of keratinocytes with basal epidermal layer characteristics using HaCaT cells and TNFα to induce inflammation. TNFα increased the gene expression of tight junction protein claudin 1 (CLDN1) by at least 2.60 ± 0.16-fold, in a concentration-dependent manner, over a 48h period. The administration of a capsaicin pre-treatment reduced the CLDN1 expression to 1.51 ± 0.16-fold during the first 6h after TNFα induction, whereas IL-8 cytokine release was reduced 0.64 ± 0.17-fold. After 48h, CLDN1 protein levels increased by a factor of 6.57 ± 1.39 compared to cells only treated with TNFα. These results suggest that activation of TRPV1 by capsaicin can potentiate the increase in CLDN1 expression and CLDN1 protein synthesis induced by TNFα in cultured keratinocytes, while reducing the release of IL-8.

Predictive Blood Biomarkers of Targeted Intervention for Chronic Mental Health Symptoms following Traumatic Brain Injury.

The purpose of this study was to assess the performance of predictive blood biomarkers for responsiveness to targeted treatments for chronic psychological issues years after traumatic brain injury (TBI). Targeted Evaluation Action and Monitoring of TBI was a prospective 6-month interventional trial of participants with chronic TBI sequelae (n = 95). Plasma biomarkers were analyzed pre-intervention: glial fibrillary acidic protein (GFAP), tau, hyperphosphorylated tau Thr231 (p-Tau), von Willebrand factor (vWF), brain lipid-binding protein (BLBP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), vascular endothelial growth factor-a (VEGFa), and claudin-5 (CLDN5). Clinical outcomes included the Post-Traumatic Stress Disorder (PTSD)Checklist for DSM-5 (PCL-5) and Brief Symptom Inventory-18 (BSI-18). Regression models were built for change in PCL5/BSI-18. Biomarkers and covariates were included. Two models were built to identify responders (improved beyond the minimum clinically important difference). The model to predict change in PCL5 (R2=0.64; p < 0.001) included vWF (p = 0.032), BLBP (p = 0.001), tau (p = 0.002), VEGFa (p = 0.015), female sex (p = 0.06), and military status (p = 0.014). The model to predict change in BSI-18 (R2=0.42; p = 0.003) included vWF (p = 0.042), VEGFa (p = 0.09), BLBP (p = 0.01), CLDN5 (p < 0.001), female sex (p = 0.012), and military status (p = 0.004) as predictors. The model to differentiate participants who improved for PCL5 (R2=0.68; p < 0.001; AUC = 0.93) included vWF (p = 0.02), VEGFa (p = 0.008), and BLBP (p = 0.006). The model to differentiate participants who improved for BSI-18 (R2=0.25; p = 0.04; AUC = 0.75) included UCH-L1 (p = 0.03), GFAP (p = 0.06), and vWF (p = 0.03). Combinations of pre-intervention blood biomarkers were able to differentiate responders from nonresponders in both post-traumatic stress and overall psychological health domains.

MiR-181a Negatively Regulates Claudin-3 to Facilitate Lateolabrax maculatus Iridovirus Replication in Lateolabrax maculatus Astroglia Cells.

Lateolabrax maculatus iridovirus (LMIV) is a variant strain of red sea bream iridovirus (RSIV), causing serious economic losses in aquaculture. Claudins (CLDNs) are major components of tight junctions (TJs) forming an important line of defense against pathogens. Our pilot miRNA-mRNA joint analysis indicated the degradation of CLDN3, as well as its interaction with miR-181a during LMIV infection. To elucidate the miR-181a/CLDN3/LMIV interactions, in vitro assays were carried out on LMB-L cells. We first confirmed that LMIV infection could decrease the expression of CLDN3, accompanied by the enhancement of permeability, suggesting the dysfunction of TJs. Contrary to the inhibition of CLDN3, the activation of miR-181a was proved, presenting a negative correlation between miR-181a and CLDN3 (Pearson r = -0.773 and p < 0.01). In addition, the influence of CLDN3 on LMIV replication was analyzed by knockdown and over-expression of CLDN3. When CLDN3 was silenced in LMB-L cells with siCLDN3-623 at 9 days post transfection (dpt), LMIV copies and titers were significantly up-regulated by 1.59-fold and 13.87-fold, respectively. By contrast, LMIV replication in LMB-L cells was reduced by 60% and 71%, post transfection with pcDNA3.1-CLDN3 over-expressed plasmid at 6 dpt and 9 dpt, respectively. Ultimately, the regulatory relationship between miR-181a and CLDN3 was further validated by dual luciferase reporter assays. Taking into account the above-described results, we proposed a "miR-181a/CLDN3/LMIV" regulatory relationship. This study provides a new insight for understanding the mechanism of LMIV replication.

SAIL66, a next generation CLDN6-targeting T-cell engager, demonstrates potent antitumor efficacy through dual binding to CD3/CD137

BackgroundOvarian cancer remains a formidable challenge in oncology, necessitating innovative therapeutic approaches. Claudin-6 (CLDN6), a member of the tight junction molecule CLDN family, exhibits negligible expression in healthy tissues but...

Long-Term Exposure of Fresh and Aged Nano Zinc Oxide Promotes Hepatocellular Carcinoma Malignancy by Up-Regulating Claudin-2.

Tumor development and progression is a long and complex process influenced by a combination of intrinsic (eg, gene mutation) and extrinsic (eg, environmental pollution) factors. As a detoxification organ, the liver plays an important role in human exposure and response to various environmental pollutants including nanomaterials (NMs). Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and remains a serious threat to human health. Whether NMs promote liver cancer progression remains elusive and assessing long-term exposure to subtoxic doses of nanoparticles (NPs) remains a challenge. In this study, we focused on the promotional effects of nano zinc oxide (nZnO) on the malignant progression of human HCC cells HepG2, especially aged nZnO that has undergone physicochemical transformation. In in vitro experiments, we performed colony forming efficiency, soft agar colony formation, and cell migration/invasion assays on HepG2 cells that had been exposed to a low dose of nZnO (1.5μg/mL) for 3 or 4 months. In in vivo experiments, we subcutaneously inoculated HepG2 cells that had undergone long-term exposure to nZnO for 4 months into BALB/c athymic nude mice and observed tumor formation. ZnCl2 was administered to determine the role of zinc ions. Chronic low-dose exposure to nZnO significantly intensified the malignant progression of HCC cells, whereas aged nZnO may exacerbate the severity of malignant progression. Furthermore, through transcriptome sequencing analysis and in vitro cellular rescue experiments, we demonstrated that the mechanism of nZnO-induced malignant progression of HCC could be linked to the activation of Claudin-2 (CLDN2), one of the components of cellular tight junctions, and the dysregulation of its downstream signaling pathways. Long-term exposure of fresh and aged nZnO promotes hepatocellular carcinoma malignancy by up-regulating CLDN2. The implications of this work can be profound for cancer patients, as the use of various nanoproducts and unintentional exposure to environmentally transformed NMs may unknowingly hasten the progression of their cancers.

Expression of claudin 18.2 in poorly cohesive carcinoma and its association with clinicopathologic parameters in East Asian patients

BackgroundPoorly cohesive carcinoma (PCC) is a distinct subtype of gastric cancer with limited therapeutic options. This study investigated claudin (CLDN) 18.2 expression status in PCCs using a 43–13 A clone. MethodsWe retrospectively collected 178 consecutive surgically resected stage Ⅱ–Ⅲ gastric cancer samples. Tissue microarray blocks were constructed for CLDN18.2 immunohistochemical staining. We studied CLDN18.2 expression and its association with clinicopathologic parameters. ResultsCLDN18.2 positivity (defined by ≥ 75 % of tumor cells showing moderate to strong membranous positivity) was found in 34.8 % of the PCC cases (62/178). Approximately half of the CLDN18.2 positive PCCs demonstrated heterogeneous expression (51.6 %, 32/62). CLDN18.2 positivity was not associated with any clinicopathologic parameters examined. However, CLDN18.2 positivity tended to be more frequent in E-cadherin-positive PCCs (no loss of expression) than in E-cadherin-negative PCCs (loss of expression) (50 % vs. 27.7 %). The CLDN18.2 expression level, represented by the H-score, gradually decreased as the paraffin block storage time increased (P = 0.046). Overall survival and disease-free survival analyses showed no significant difference between CLDN18.2-positive and negative PCCs. ConclusionsA significant portion of surgically resected PCC specimens showed CLDN18.2 positivity. Additionally, since the expression level of CLDN18.2 gradually decreases with increased paraffin block storage time, reflex testing can be considered at the time of the cancer diagnosis.

610O Preliminary results from a phase I, first-in-human study of DS-9606a, a claudin 6 (CLDN6)-directed antibody-drug conjugate (ADC), in patients (pts) with tumor types known to express CLDN6

610O Preliminary results from a phase I, first-in-human study of DS-9606a, a claudin 6 (CLDN6)-directed antibody-drug conjugate (ADC), in patients (pts) with tumor types known to express CLDN6

721MO Phase I, two-part, multicenter first-in-human (FIH) study of TORL-1-23: A novel claudin 6 (CLDN6) targeting antibody drug conjugate (ADC) in patient with advanced solid tumors

721MO Phase I, two-part, multicenter first-in-human (FIH) study of TORL-1-23: A novel claudin 6 (CLDN6) targeting antibody drug conjugate (ADC) in patient with advanced solid tumors

924P Claudin-1 (CLDN1) tight junction protein expression delineates distinct immune infiltrates in ascending (A) vs descending (D) subtypes of nasopharyngeal carcinoma: Potential implications for treatment selection

924P Claudin-1 (CLDN1) tight junction protein expression delineates distinct immune infiltrates in ascending (A) vs descending (D) subtypes of nasopharyngeal carcinoma: Potential implications for treatment selection

Claudin-1 in head and neck squamous cell carcinoma

Introduction. The objective response rate to immunotherapy is limited in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) patients, whose prognosis is still dismal. Few prognostic factors are clinically available, mostly related to patient or disease characteristics. Gene expression signatures offer better prognostic abilities but are mainly used in research. One such GE model classifies HNSCC into 6 clusters with different prognoses. Claudin-1 (CLDN1), which influences tumor microenvironment and immune cell infiltration, has emerged as a potential target, especially in cancers like HNSCC with high CLDN1 expression. Methods. A single-center cohort of 100 loco-regionally advanced HNSCC patients from the BD2Decide observational study was analyzed. Patients were selected to balance long-term survivors and deceased patients, including HPV-negative and HPV-positive cases. Primary tumor specimens underwent GE analysis using Affymetrix ClariomD chips. Primary endpoint was overall survival (OS). Results. The cohort comprised 100 HNSCC patients with a median age of 60 years, predominantly men (76%). Median OS and DFS were 94.24 and 42.79 months, respectively. CLDN1 expression varied significantly among primary sites, being highest in hypopharynx cancers. Differences in expression were not significant when stratified by HPV status or clinical stage. CLDN1 expression differed across the 6 transcriptomic clusters, with the highest levels in clusters associated with mesenchymal and hypoxic features. Higher CLDN1 expression correlated with shorter OS (HR 3, p=0.0023) and DFS (HR 2.14, p=0.02). Conclusion. CLDN1 expression is heterogeneous in HNSCC and carries prognostic significance. It is highest in tumors with HPV-like biology and hypoxic environments, and lowest in immune-sensitive clusters. High CLDN1 is a negative prognostic factor and a promising therapeutic target. Anti-CLDN1 treatments could improve outcomes of CLDN1+ HNSCC patients, and combination therapies with ICIs might overcome resistance in CLDN1- cases. These findings support the need for clinical studies on anti-CLDN1 therapies.