Deciphering The Complex Circulating Immune Cell Microenvironment in Chronic Lymphocytic Leukemia Using Patient Similarity Networks

Deciphering The Complex Circulating Immune Cell Microenvironment in Chronic Lymphocytic Leukemia Using Patient Similarity Networks | 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 Deciphering The Complex Circulating Immune Cell Microenvironment in Chronic Lymphocytic Leukemia Using Patient Similarity Networks Zuzana Mikulkova, Gayane Manukyan, Peter Turcsanyi, Renata Urbanova, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-40236/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The tissue microenvironment in chronic lymphocytic leukemia (CLL) plays a key role in promoting neoplastic cell survival, proliferation, and drug resistance. There is a lack of complex characterization of CLL blood microenvironment and its clinical impact. Methods: Immunophenotypic profiles of circulating immune cells in 244 CLL patients (untreated, n=123; novel agents, n=67; previous immunochemotherapy, n=54) and age/sex-matched healthy controls (n=52) were assessed using flow cytometry and analyzed by multivariate patient similarity networks (PSNs). Results: Our study revealed high inter-individual heterogeneity in distribution and activation status of bystander immune cells in CLL, depending on the bulk of CLL cells. High CLL counts were associated with low activation status on circulating monocytes, T and NK cells and vice versa low CLL counts with high activation of immune cells, reaching levels in controls. Regarding treatment, the highest activation of immune cells, particularly of intermediate and non-classical monocytes, was evident in patients treated with novel agents. Clustering and visualization using PSNs confirmed low activation of immune cells in progressive disease, irrespectively of IgHV status and Binet stage. Calculating time-to-event endpoint, patients with high intermediate monocytes (>5.4%), predominantly low activated, were associated with 2.5-fold higher likelihood (95% CI 1.421-4.403, P =0.002) of event than those with low percentage of intermediate monocytes. Conclusions: Activation of circulating immune cells are dependent on the CLL cell counts and used therapy, with the lowest activation in patients with progressive disease. Percentage and activation of intermediate monocytes could be of prognostic value in CLL. Cancer Biology Hematology Intermediate monocytes Peripheral blood microenvironment Patient similarity network Immune cell activation Novel agents Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Full Text Supplementary Files MikulkovaJEXPCLINCANCRESSuppl.pdf MikulkovaJEXPCLINCANCRESSuppl.pdf Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-40236","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":769504,"identity":"9767c709-5de7-429a-9677-f34ebc14da3e","order_by":0,"name":"Zuzana Mikulkova","email":"","orcid":"","institution":"Univerzita Palackeho v Olomouci Lekarska fakulta","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zuzana","middleName":"","lastName":"Mikulkova","suffix":""},{"id":769505,"identity":"60cfbc7a-91a1-44f2-9429-3511ca5d5ca7","order_by":1,"name":"Gayane Manukyan","email":"","orcid":"","institution":"Univerzita Palackeho v 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Olomouci","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Eva","middleName":"","lastName":"Kriegova","suffix":""}],"badges":[],"createdAt":"2020-07-06 11:59:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-40236/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-40236/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":1506191,"identity":"3a5345ab-2073-459b-96ab-21dff31d8f37","added_by":"auto","created_at":"2020-07-07 13:29:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1215508,"visible":true,"origin":"","legend":"A) Patient similarity network (PSN) showing the distribution of CLL patients into four clusters according to percentage and CLL cell counts and expression of HLA-DR on CLL cells and subsets of monocytes (classical, intermediate, non-classical MON). Individual clusters are colored; each node corresponds to one patient; lines connect patients with the highest similarity of expression/cell count profiles. B) Characteristics of obtained clusters revealed by PSN. The y-axis in the graph shows the average values of the used markers/cell counts normalized to the maximum value in the data set.","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1/Fig1.jpg"},{"id":1506192,"identity":"33b42c5b-d111-4197-8688-dd7932c41e23","added_by":"auto","created_at":"2020-07-07 13:29:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":626195,"visible":true,"origin":"","legend":"Heat map illustrating negative correlations of activation markers on immune cells with the CLL cell counts. Each column represents an individual CLL patient. Patients are ranked according to the CLL cell counts (x109cells/L) from the lowest (green) to the highest (red) values. The expression (MFI) of HLA-DR and CD64 on the populations were colored according to the range of values of individual populations from the lowest (green) to the highest (red) values.","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1/Fig2.jpg"},{"id":1506193,"identity":"8ccfbc01-14e6-4cea-9564-04e07f4484a5","added_by":"auto","created_at":"2020-07-07 13:29:37","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1832145,"visible":true,"origin":"","legend":"The relationship between immune cell activation and clinical parameters in CLL\npatients. Clustering was performed using PSN on a combination of HLA-DR expression on monocytes subsets, CD4+ and CD8+ lymphocytes and NK cells. A) The trend of changes in activation of immune subpopulations across the patient clusters. The dots represent individual CLL patients colored according to B) CLL cell counts; C) treatment regime; D) novel drugs\ntreatment; E) treatment requirement in treatment-naïve patients; F) IgHV mutational status.","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1/Fig3.jpg"},{"id":1506194,"identity":"735bd3f6-60c9-4f7b-89ff-9823ab262566","added_by":"auto","created_at":"2020-07-07 13:29:38","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":922226,"visible":true,"origin":"","legend":"Time-dependent changes of CLL counts, percentages of intermediate monocytes and their expression of HLA-DR and CD64 in A) ibrutinib (IBR, n=5) and B) idelalisib (IDEL, n=6) treated patients. CLL cell counts is shown by red dots and curves (5th-degree polynomial regression), expression of HLA-DR and CD64 on intermediate monocytes is shown by blue and violet graphs, respectively, and percentages of intermediate monocytes is shown by black dots and curves. Some patients were not sampled at all-time points.","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1/Fig4.jpg"},{"id":1506195,"identity":"fc4ebee6-b996-41eb-9710-76a4dba734df","added_by":"auto","created_at":"2020-07-07 13:29:38","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":651859,"visible":true,"origin":"","legend":"Distribution of circulating cells in treatment-naïve (TN) CLL patients who required treatment within 1 year (TN-T), TN patients with the indolent course (TN) and healthy controls (HC). A) CLL cell counts in CLL patients or B cells in healthy controls, B) percentages of intermediate monocytes and proportion of Treg cells within CD4+ T cells, and C) expression of HLA-DR on classical, intermediate and non-classical monocytes (MON). In some patients, values are missing due to the low proportion of some immune populations.","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1/Fig5.jpg"},{"id":1506196,"identity":"86beda23-8d6c-4709-a66c-4a894e08d4d6","added_by":"auto","created_at":"2020-07-07 13:29:38","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":497258,"visible":true,"origin":"","legend":"Prognostic potential of intermediate monocyte percentage in CLL patients. A) ROC curve for TN patients sampled at the diagnosis subdivided according to the time-to-event endpoint (TTE) during the post-sampling follow-up. Kaplan-Meier curves show TTE (green curve for patients with a low percentage of intermediate MON, while red curve is for patients with more than 5.4% of intermediate MON) in groups of B) newly diagnosed TN patients and C) validation cohort of CLL patients in all stages of the disease.","description":"","filename":"Fig6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1/Fig6.jpg"},{"id":13513475,"identity":"4ed6eb10-e06b-4225-a668-f2b4e116bfab","added_by":"auto","created_at":"2021-09-16 23:59:37","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1150322,"visible":true,"origin":"","legend":"","description":"","filename":"MikulkovaJEXPCLINCANCRES.pdf","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1_covered.pdf"},{"id":1506197,"identity":"1eeb908f-4058-4480-b120-b79c6c69faa8","added_by":"auto","created_at":"2020-07-07 13:29:38","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":848200,"visible":true,"origin":"","legend":"","description":"","filename":"MikulkovaJEXPCLINCANCRES.pdf","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1/MikulkovaJEXPCLINCANCRES.pdf"},{"id":1506190,"identity":"66b65fc5-e589-4f00-bce9-b98e48fc5b0e","added_by":"auto","created_at":"2020-07-07 13:29:36","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":878492,"visible":true,"origin":"","legend":"","description":"","filename":"MikulkovaJEXPCLINCANCRES.pdf","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1_stamped.pdf"},{"id":1506188,"identity":"6f0c6d71-adff-43e4-8c23-6dd20f06cfe5","added_by":"auto","created_at":"2020-07-07 13:29:35","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":848200,"visible":true,"origin":"","legend":"","description":"","filename":"MikulkovaJEXPCLINCANCRES.pdf","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1/MikulkovaJEXPCLINCANCRES.pdf"},{"id":1506198,"identity":"d7a446df-040b-404b-af32-e3de014ba9ee","added_by":"auto","created_at":"2020-07-07 13:29:38","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":743789,"visible":true,"origin":"","legend":"","description":"","filename":"MikulkovaJEXPCLINCANCRESSuppl.pdf","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1/MikulkovaJEXPCLINCANCRESSuppl.pdf"},{"id":1506189,"identity":"3bc9da22-33f0-4f49-890d-2a42b24f1f70","added_by":"auto","created_at":"2020-07-07 13:29:35","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":743789,"visible":true,"origin":"","legend":"","description":"","filename":"MikulkovaJEXPCLINCANCRESSuppl.pdf","url":"https://assets-eu.researchsquare.com/files/rs-40236/v1/MikulkovaJEXPCLINCANCRESSuppl.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eDeciphering The Complex Circulating Immune Cell Microenvironment in Chronic Lymphocytic Leukemia Using Patient Similarity Networks\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-40236/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Intermediate monocytes, Peripheral blood microenvironment, Patient similarity network, Immune cell activation, Novel agents","lastPublishedDoi":"10.21203/rs.3.rs-40236/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-40236/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe tissue microenvironment in chronic lymphocytic leukemia (CLL) plays a key role in promoting neoplastic cell survival, proliferation, and drug resistance. There is a lack of complex characterization of CLL blood microenvironment and its clinical impact. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Immunophenotypic profiles of circulating immune cells in 244 CLL patients (untreated, n=123; novel agents, n=67; previous immunochemotherapy, n=54) and age/sex-matched healthy controls (n=52) were assessed using flow cytometry and analyzed by multivariate patient similarity networks (PSNs). \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Our study revealed high inter-individual heterogeneity in distribution and activation status of bystander immune cells in CLL, depending on the bulk of CLL cells. High CLL counts were associated with low activation status on circulating monocytes, T and NK cells and vice versa low CLL counts with high activation of immune cells, reaching levels in controls. Regarding treatment, the highest activation of immune cells, particularly of intermediate and non-classical monocytes, was evident in patients treated with novel agents. Clustering and visualization using PSNs confirmed low activation of immune cells in progressive disease, irrespectively of IgHV status and Binet stage. Calculating time-to-event endpoint, patients with high intermediate monocytes (\u0026gt;5.4%), predominantly low activated, were associated with 2.5-fold higher likelihood (95% CI 1.421-4.403, P =0.002) of event than those with low percentage of intermediate monocytes. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Activation of circulating immune cells are dependent on the CLL cell counts and used therapy, with the lowest activation in patients with progressive disease. Percentage and activation of intermediate monocytes could be of prognostic value in CLL.\u003c/p\u003e","manuscriptTitle":"Deciphering The Complex Circulating Immune Cell Microenvironment in Chronic Lymphocytic Leukemia Using Patient Similarity Networks","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-07-07 13:29:33","doi":"10.21203/rs.3.rs-40236/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"834e19f6-5d45-4c6c-addc-507e903fa56a","owner":[],"postedDate":"July 7th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":144189,"name":"Cancer Biology"},{"id":144190,"name":"Hematology"}],"tags":[],"updatedAt":"2020-07-07T13:29:34+00:00","versionOfRecord":[],"versionCreatedAt":"2020-07-07 13:29:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-40236","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-40236","identity":"rs-40236","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}