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Carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1), a homotypic cell adhesion molecule glycoprotein with apical expression on normal epithelial cells and activated lymphocytes, is overexpressed on many tumors and acts as an inhibitory receptor on NK cells, preventing their killing of CEACAM1 positive tumors. Production of humanized anti-CEACAM1 antibodies to block the inhibitory activity of CEACAM1 for immunotherapy and immunoimaging. Starting from a scFv, a fully human intact anti-CEACAM1 (DIA 12.3) that recognizes the N-terminal domain of CEACAM1 was developed and shown to bind CEACAM1 positive tumor cells and enhanced NK cell killing of CEACAM1 positive targets. DIA 12.3 bound to human neutrophils without activation, indicating they would be safe for human use. DIA 12.3 exhibited some cross-reactivity to CEACAM5, a tumor marker with high sequence homology to the N-terminal domain of CEACAM1. CEACAM1 PET imaging with 64 Cu-COTA-DIA 12.3 showed excellent imaging of CEACAM1 positive tumors with reduced binding to CEACAM5 tumors. Based on its immunoinhibitory an immunoimaging activities, DIA 12.3 shows promise for therapeutic studies in man.

Translational medicine remains one of the central challenges in modern biomedical research. A major bottleneck in this field is the limited availability of suitable animal models that reliably predict human disease outcomes. Large animal models, particularly pigs, are increasingly recognized as promising preclinical systems for translating fundamental immunological and oncological discoveries into clinically relevant applications. Given the pivotal role of the carcinoembryonic antigen (CEA) family, both as key regulators of immune responses (e.g., CEACAM1) and as tumor antigens (e.g., CEA) in humans, we performed a comprehensive characterization of the porcine CEA gene family. By generating monoclonal antibodies specific for individual porcine CEACAMs, we analyzed the expression of porcine CEACAMs in tissues and culture supernatants. Our analyses identified the ortholog of CEACAM1 as well as a GPI-anchored CEACAM (CEACAM60), a homolog of human CEA. We demonstrated that CEACAM1 is expressed on various immune cell populations, consistent with patterns observed in humans. Furthermore, we found that CEACAM60 is selectively expressed at the apical membrane of enterocytes in the large intestine, mirroring the expression topology described for human CEA. Strict apical localization in healthy epithelial tissues results in the release of CEACAM60 into the intestinal lumen, thereby preventing its presence in systemic body fluids. In contrast, in malignant tissues, loss of cellular differentiation and disruption of apical-basal polarity abolish this compartmentalization, providing the essential prerequisite for the occurrence of CEACAM60 in serum under neoplastic conditions. Based on these findings, we developed a detection assay for CEACAM60 in fluids, which could serve as a basis for dynamic monitoring of tumor progression in animals in the future. Considering the central roles of CEACAM1 and CEA in tumor immunotherapy and tumor surveillance in humans, porcine models with an increased predisposition for colorectal neoplasia may provide a valuable translational platform for the development and refinement of next-generation colorectal cancer immunotherapies.

T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) expression has been a trending topic in recent years due to its differential expression in a wide range of neoplasms. TIM-3 is one of the key immune checkpoint receptors that interact with GAL-9, PtdSer, HMGB1 and CEACAM1. Initially identified on the surface of T helper 1 (Th1) lymphocytes and later on cytotoxic lymphocytes (CTLs), monocytes, macrophages, natural killer cells (NKs), and dendritic cells (DCs), TIM-3 plays a key role in immunoregulation. Recently, a growing body of evidence has shown that its differential expression in various tumor types indicates a specific prognosis for cancer patients. Here, we discuss which types of cancer TIM-3 can serve as a prognostic factor and the influence of coexpressed immune checkpoint inhibitors, such as LAG-3, PD-1, and CTLA-4 on patients' outcomes. Currently, experimental medicine involving TIM-3 has significantly enhanced the anti-tumor effect and improved patient survival. In this work, we summarized clinical trials incorporating TIM-3 targeting monoclonal and bispecific antibodies in monotherapy and combination therapy and highlighted the emerging role of cell-based therapies.

Immunosuppressive molecules are extremely valuable prognostic biomarkers across different cancer types. However, the diversity of different immunosuppressive molecules makes it very difficult to accurately predict clinical outcomes based only on a single immunosuppressive molecule. Here, we establish a comprehensive immune scoring system (ISS GC ) based on 6 immunosuppressive ligands (NECTIN2, CEACAM1, HMGB1, SIGLEC6, CD44, and CD155) using the LASSO method to improve prognostic accuracy and provide an additional selection strategy for adjuvant chemotherapy of gastric cancer (GC). The results show that ISS GC is an independent prognostic factor and a supplement of TNM stage for GC patients, and it can improve their prognosis prediction accuracy; in addition, it can distinguish GC patients with better prognosis from those with high prognostic nutritional index score; furthermore, ISS GC can also be used as a tool to select GC patients who would benefit from adjuvant chemotherapy independent of their TNM stages, MSI status and EBV status. Expression patterns of immune checkpoints in patients with gastric cancer remain poorly characterized. Here the authors propose an immune scoring system based on the expression of six immunosuppressive ligands to improve the prognostic accuracy in gastric cancer patients and drive the selection of candidates for adjuvant chemotherapy.

Transfer RNA‐derived fragments are a group of small noncoding single‐stranded RNA that play essential roles in multiple diseases. However, their biological functions in carcinogenesis are not well understood. In this study, 5′tRF‐Gly was found to have significantly high expression in hepatocellular carcinoma (HCC), and the upregulation of 5′tRF‐Gly was positively correlated with tumor size and tumor metastasis. Overexpression of 5′tRF‐Gly induced increased growth rate and metastasis in HCC cells in vitro and in nude mice, while knockdown showed the opposite effect. Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) was confirmed to be a direct target of 5′tRF‐Gly in HCC. In addition, the cytological effect of CEACAM1 knockdown proved to be similar to the overexpression of 5′tRF‐Gly. Moreover, attenuation of CEACAM1 expression rescued the 5′tRF‐Gly‐mediated promoting effects on HCC cells. These data show that 5′tRF‐Gly is a new tumor‐promoting factor and could be a potential diagnostic biomarker or new therapeutic target for HCC. In the present study, the small RNA high‐throughput sequencing results showed that 5’tRF‐Gly was up‐regulated in HCC tissues and was related to poor prognosis. We demonstrated the oncogenic role of 5’tRF‐Gly and its underlying molecular mechanism in HCC. Furthermore, we first verified CEA cell adhesion molecule 1 (CEACAM1) as the direct target of 5’tRF‐Gly and revealed how CEACAM1 inhibits hepatocellular carcinoma growth and metastasis. Our findings not only elucidate the role of 5’tRF‐Gly and CEACAM1 in HCC but also provide new targets for the prognostic evaluation and treatment of HCC.

Chronic inflammation with progressive age, called inflammaging, contributes to the pathogenesis of cardiovascular diseases. Previously, we have shown increased vascular expression of the Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) in aged mice and humans, presumably via mutual upregulation with the pro‐inflammatory cytokine TNF‐α. CEACAM1 is critical for aging‐associated vascular alterations like endothelial dysfunction, fibrosis, oxidative stress, and sustained inflammation and can be regarded as a main contributor to vascular inflammaging. This study was conducted to elucidate the mechanisms underlying endothelial CEACAM1 upregulation by TNF‐α in detail. Using wildtype (WT) and TNF‐α knockout (Tnf−/−) mice, we confirmed that the aging‐related upregulation of endothelial CEACAM1 critically depends on TNF‐α. The underlying mechanisms were analyzed in an endothelial cell culture model. TNF‐α time‐dependently upregulated CEACAM1 in vitro. In pharmacological experiments, we identified an early NF‐κB‐ and a delayed β‐catenin‐mediated response. Involvement of β‐catenin was further substantiated by siRNA‐mediated knockdown of the β‐catenin‐targeted transcription factor TCF4. Both signaling pathways acted independent from each other. Elucidating the delayed response, co‐immunoprecipitation analysis revealed release of β‐catenin from adherens junctions by TNF‐α. Finally, TNF‐α activated Akt kinase by increasing its Ser473 phosphorylation. Consequently, Akt kinase facilitated β‐catenin signaling by inhibiting its degradation via phosphorylation of GSK3β at Ser9 and by increased phosphorylation of β‐catenin at Ser552 that augments its transcriptional activity. Taken together, our study provides novel mechanistic insights into the aging‐related, inflammation‐mediated endothelial upregulation of CEACAM1. Beyond the pathogenesis of cardiovascular diseases, these findings may be significant to all fields of inflammaging. Early response: TNF‐α activates NF‐κB signaling by IKK‐induced degradation of the inhibitor of nuclear factor kappa B (IκB). Released NF‐κB translocates into the nucleus and upregulates CEACAM1 expression detectable after 24 h of TNF‐α stimulation. Delayed response: TNF‐α‐induced adherens junction disassembly releases β‐catenin, promoting its cytosolic and nuclear accumulation. Nuclear β‐catenin binds to transcription factors of the TCF/LEF family to induce CEACAM1 expression. Akt kinase inhibits GSK3β by phosphorylation thereby stabilizing β‐catenin and directly phosphorylates β‐catenin which was reported to increase its transcriptional activity.

F. nucleatum is an anaerobic bacterium that is associated with several tumor entities and promotes tumorigenesis. Recent evidence suggests that F. nucleatum binds the inhibitory receptor carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) via the trimeric autotransporter adhesin CbpF. However, whether this binding is functional or whether other fusobacterial trimeric autotransporter adhesins are involved in CEACAM1 activation is unknown. In this study, using F. nucleatum mutants lacking the type 5c trimeric autotransporter adhesins fvcA (CbpF), fvcB, fvcC, and fvcD, we show that F. nucleatum CbpF binds and activates CEACAM1 and also binds carcinoembryonic antigen (CEA), a tumor-associated protein. We further find that CEACAM antibodies directed against the CEACAM N-terminal domain block the CbpF-CEACAM1 interaction. In functional assays, we demonstrate CbpF-dependent inhibition of CD4 + T cell response. Thus, we characterize an immune evasion mechanism in which F. nucleatum uses its surface protein CbpF to inhibit T cell function by activating CEACAM1.

The Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as CD66a, is a member of the immunoglobulin superfamily. CEACAM1 was shown to be a prognostic marker in patients suffering from cancer. In this review, we summarize pre-clinical and clinical evidence linking CEACAM1 to tumorigenicity and cancer progression. Furthermore, we discuss potential CEACAM1-based mechanisms that may affect cancer biology.

Background: Pancreatic cancer is an aggressive malignancy with poor survival. Most patients are diagnosed at advanced or metastatic stages because early disease is often asymptomatic and effective screening tools are lacking. We evaluated a three-marker model comprising serum CA19-9 in combination with the plasma proteins ITIH3 and CEACAM1 for pancreatic ductal adenocarcinoma (PDAC) detection. Methods: Matched plasma and serum samples were collected from 649 participants (250 PDAC cases and 399 controls). Plasma proteins were enriched using high-surface area magnetic covalent organic framework (COF) polymers. Serum CA19-9 was measured using the Tosoh Bioscience immunoassay. The marker panel was trained using a radial-based SVM with repeated 10-fold cross-validation using a set-aside training sample set. The derived model along with a fixed cutoff corresponding to 95% sensitivity in training samples were independently validated using a blinded sample set. Results: In the independent blinded validation, the combined panel of serum CA19-9 with plasma ITIH3 and CEACAM1 achieved an AUC of 0.917 indicating that the three-marker panel maintained strong performance in distinguishing PDAC from controls. At the prefixed threshold, the three-marker panel had a specificity of 53.3% (95% CI: 46.8–59.7%), significantly outperforming CA19-9 alone at 14.5% (95% CI: 10.4–19.7%). Conclusions: In independently blinded validation, combining plasma ITIH3 and CEACAM1 with serum CA19-9 substantially improved diagnostic performance for PDAC, achieving high specificity while maintaining 95% sensitivity compared with serum CA19-9 alone. These findings support further validation of this three-marker panel as a potential PDAC monitoring and detection approach in larger, multicenter studies.

Early detection and long‐term monitoring are important for urothelial carcinoma of the bladder (UCB). Urine cytology and existing markers have insufficient diagnostic performance. Here, we examined medium‐sized extracellular vesicles (EVs) in urine to identify specific markers for UCB and evaluated their usefulness as diagnostic material. To identify specific markers in urinary EVs derived from UCB, we undertook shotgun proteomics using urine from four UCB patients and four healthy subjects. Next, 29 healthy specimens, 18 noncancer specimens, and 33 UCB specimens, all from men, were analyzed for urinary EVs by flow cytometry to evaluate the diagnostic performance of UCB‐specific EVs. Nanoparticle‐tracking analysis indicated that the size of EVs extracted from urine was mostly <400 nm. By shotgun proteomics, we detected several proteins characteristic of UCB and found that carcinoembryonic antigen‐related adhesion molecule (CEACAM) proteins were increased in patients. Flow cytometric analysis revealed that the degree of expression of CEACAM1, CEACAM5, and CEACAM6 proteins on the surface of EVs varied among patients. Extracellular vesicles expressing CEACAM proteins also expressed mucin 1, suggesting that they were derived from tumorigenic uroepithelial cells. The number of EVs expressing CEACAM1, 5, and 6 proteins was significantly increased in UCB (mean ± SD, 8.6 ± 13%) compared to non‐UCB (0.69 ± 0.46) and healthy (0.46 ± 0.34) by flow cytometry. The results of receiver operating characteristic (ROC) analysis showed a good score of area under the ROC curve of 0.907. We identified EVs that specifically express CEACAM proteins in urine and have potential for diagnostic applications. These EVs are potential targets in a new liquid biopsy test for UCB patients. ・Increased CEACAM proteins was found in EV fraction of urine from patients with bladder cancer by shotgun proteomics. ・Urinary EVs expressing CEACAM proteins, characterized by flow cytometry, are also accompanied by MUC1, which is increased in patients with bladder cancer. ・EVs expressing CEACAM proteins in urine have good diagnostic performance to detect bladder cancer patients.