Extracellular NAD + Modulates CD203a Expression on Th17 Cells and Predicts Long-Term Recurrence-Free Survival in Hepatocellular Carcinoma

Extracellular NAD + Modulates CD203a Expression on Th17 Cells and Predicts Long-Term Recurrence-Free Survival in Hepatocellular Carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Extracellular NAD + Modulates CD203a Expression on Th17 Cells and Predicts Long-Term Recurrence-Free Survival in Hepatocellular Carcinoma Julia Babigian, Philipp Brunnbauer, Can Kamali, Sebastian Knitter, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5819446/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Mar, 2025 Read the published version in Journal of Cancer Research and Clinical Oncology → Version 1 posted 11 You are reading this latest preprint version Abstract Background and Aims: Mortality rates for hepatocellular carcinoma (HCC) remain high, while multimodal treatment approaches offer new perspectives. Here, we investigated the influence of extracellular nicotinamide adenine dinucleotide (eNAD +) on ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (CD203a, ENPP1 or PC-1) on Th17 cells in relation to the likelihood of HCC recurrence following liver resection. Method: The study compared heparinized blood plasma samples from 95 patients who underwent liver resection, including 20 patients with HCC and 10 control patients without liver disease. Plasma eNAD + concentrations were determined using a heat-based dichotomous pH extraction method, followed by enzymatic cycling and a colorimetric assay for quantification. Fibrosis was graded histologically using the Desmet score (F0-F4). Surface expression analysis was performed using flow cytometry. Results: With increasing grades of liver fibrosis grade a significant reduction in plasma eNAD + concentrations was measured (p < 0.05). Further, a significant correlation was found between eNAD + levels and CD203a expression on CD4 + , CCR4 + as well as CCR6 + T cells (p < 0.05). Patients who exhibited high proportions of CD203a expressing Th17 cells (CD4 + , CCR6 + CCR4 +) post surgery were found to be at a 6-fold increased risk (HR 6.38, 95% Cl 1,51-27.00) of HCC recurrence and had a median recurrence-free survival of 233 days (p < 0.05), compared to patients with low CD203a expressing Th17 cells (CD4 + CCR6 + CCR4 +). Similarly, patients who had a high proportion of CD203a expressing Th17 cells (CD4 + CCR6 +) following surgery had a 5-fold increased risk (HR 5.56, 95% Cl 1.58-19.59) of HCC recurrence and a median recurrence-free survival of 334 days (p < 0.05) compared to those with low CD203a expressing Th17 cells (CCR6 +). Conclusion: The data indicate that eNAD + levels are decreased in patients with liver fibrosis or cirrhosis, and are correlated with the expression of ectoenzyme CD203a on Th17 cells. Consequently, patients with high expression of CD203a on Th17 cells had a significantly increased likelihood of recurrence, indicating their potential as valuable prognostic markers and a possible therapeutic target. Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 19 Mar, 2025 Read the published version in Journal of Cancer Research and Clinical Oncology → Version 1 posted Editorial decision: Revision requested 14 Feb, 2025 Reviews received at journal 14 Feb, 2025 Reviews received at journal 10 Feb, 2025 Reviews received at journal 08 Feb, 2025 Reviewers agreed at journal 05 Feb, 2025 Reviewers agreed at journal 05 Feb, 2025 Reviewers agreed at journal 04 Feb, 2025 Reviewers invited by journal 15 Jan, 2025 Editor assigned by journal 15 Jan, 2025 Submission checks completed at journal 15 Jan, 2025 First submitted to journal 13 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5819446","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":402562883,"identity":"e289b6f9-72d8-49f7-855d-3f2044445732","order_by":0,"name":"Julia Babigian","email":"data:image/png;base64,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","orcid":"","institution":"Charité - 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Here, we investigated the influence of extracellular nicotinamide adenine dinucleotide (eNAD +) on ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (CD203a, ENPP1 or PC-1) on Th17 cells in relation to the likelihood of HCC recurrence following liver resection. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethod: The study compared heparinized blood plasma samples from 95 patients who underwent liver resection, including 20 patients with HCC and 10 control patients without liver disease. Plasma eNAD + concentrations were determined using a heat-based dichotomous pH extraction method, followed by enzymatic cycling and a colorimetric assay for quantification. Fibrosis was graded histologically using the Desmet score (F0-F4). Surface expression analysis was performed using flow cytometry.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: With increasing grades of liver fibrosis grade a significant reduction in plasma eNAD + concentrations was measured (p \u0026lt; 0.05). Further, a significant correlation was found between eNAD + levels and CD203a expression on CD4 + , CCR4 + as well as CCR6 + T cells (p \u0026lt; 0.05). Patients who exhibited high proportions of CD203a expressing Th17 cells (CD4 + , CCR6 + CCR4 +) post surgery were found to be at a 6-fold increased risk (HR 6.38, 95% Cl 1,51-27.00) of HCC recurrence and had a median recurrence-free survival of 233 days (p \u0026lt; 0.05), compared to patients with low CD203a expressing Th17 cells (CD4 + CCR6 + CCR4 +). Similarly, patients who had a high proportion of CD203a expressing Th17 cells (CD4 + CCR6 +) following surgery had a 5-fold increased risk (HR 5.56, 95% Cl 1.58-19.59) of HCC recurrence and a median recurrence-free survival of 334 days (p \u0026lt; 0.05) compared to those with low CD203a expressing Th17 cells (CCR6 +).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusion: The data indicate that eNAD + levels are decreased in patients with liver fibrosis or cirrhosis, and are correlated with the expression of ectoenzyme CD203a on Th17 cells. Consequently, patients with high expression of CD203a on Th17 cells had a significantly increased likelihood of recurrence, indicating their potential as valuable prognostic markers and a possible therapeutic target.\u003c/p\u003e","manuscriptTitle":"Extracellular NAD + Modulates CD203a Expression on Th17 Cells and Predicts Long-Term Recurrence-Free Survival in Hepatocellular Carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-17 14:06:02","doi":"10.21203/rs.3.rs-5819446/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-02-14T15:58:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-14T06:58:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-10T20:04:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-08T09:48:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"146570438720584596009918605909442359250","date":"2025-02-05T13:49:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"101194184047338243819026186856623960483","date":"2025-02-05T13:16:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"298176685583135889493086777817055679505","date":"2025-02-04T21:54:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-01-15T14:54:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-15T12:13:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-15T12:13:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cancer Research and Clinical Oncology","date":"2025-01-13T11:13:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"be17f5e4-f470-4154-8bd9-c9c0bf3f1c4c","owner":[],"postedDate":"January 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-24T16:08:25+00:00","versionOfRecord":{"articleIdentity":"rs-5819446","link":"https://doi.org/10.1007/s00432-025-06155-4","journal":{"identity":"journal-of-cancer-research-and-clinical-oncology","isVorOnly":false,"title":"Journal of Cancer Research and Clinical Oncology"},"publishedOn":"2025-03-19 15:57:33","publishedOnDateReadable":"March 19th, 2025"},"versionCreatedAt":"2025-01-17 14:06:02","video":"","vorDoi":"10.1007/s00432-025-06155-4","vorDoiUrl":"https://doi.org/10.1007/s00432-025-06155-4","workflowStages":[]},"version":"v1","identity":"rs-5819446","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5819446","identity":"rs-5819446","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}