Adrenergic stress misdirects erythropoiesis compromising cancer immunity

Adrenergic stress misdirects erythropoiesis compromising cancer immunity | 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 Biological Sciences - Article Adrenergic stress misdirects erythropoiesis compromising cancer immunity Pramod Srivastava, Arshmeet Chawla, Harry Sun, Sathvika Gunturu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7435097/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Psychological stress is well known to cause weaker immunity. Stress, through the hypothalamus-pituitary-adrenal axis, induces secretion of cortisol, which causes immune suppression. Recently, stress-induced adrenergic mechanisms have begun to be shown to mediate immune suppression. Our work here reveals a novel axis whereby stress modulates erythropoiesis via the fight-or-flight hormones, and through it, immune suppression. Elevated levels of catecholamines, acting through 2-adrenergic receptors on precursor cells in erythroid differentiation, mis-direct erythroid differentiation causing accumulation of aberrant erythroid precursor cells (EPC) in mice as well as humans. EPC suppress priming as well as expansion of the CD8+ T cell response through their effect on dendritic cells (DC); EPC trogocytose cell surface MHC I from DC, and DC exposed to EPC are less effective at T cell activation. EPC suppress tumor immunity in several models and this suppression is exacerbated during adrenergic stress. The magnitude of suppression of tumor immunity by EPC is comparable to that mediated by regulatory T cells. Higher expression of CD71, a marker for EPC, is associated with poor overall and disease free survival in many human cancers. Our results uncover a role for adrenergic signaling in erythropoiesis, and establish erythroid cells, in addition to the lymphoid and myeloid cells, as significant determinants of cancer immunity. Biological sciences/Immunology/Haematopoiesis/Erythropoiesis Health sciences/Medical research/Stem-cell research sympathetic nervous system erythroid dendritic cells stress trogocytosis Full Text Additional Declarations There is NO Competing Interest. Supplementary Files S1DCEPC.mp4 EPC (red) trogocytose surface proteins from DC (green) S2DCRBC.mp4 RBC (red) do not trogocytose surface proteins from DC (green) S3DCFibroblasts.mp4 Fibroblasts (red) do not trogocytose surface proteins from DC (green) S4EPCFibroblasts.mp4 EPC (red) do not trogocytose surface proteins from fibroblasts (green) Cite Share Download PDF Status: Under Review 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-7435097","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":523435820,"identity":"0703546c-aa88-4806-b57b-8d5509d370c2","order_by":0,"name":"Pramod 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Stress, through the hypothalamus-pituitary-adrenal axis, induces secretion of cortisol, which causes immune suppression. Recently, stress-induced adrenergic mechanisms have begun to be shown to mediate immune suppression. Our work here reveals a novel axis whereby stress modulates erythropoiesis via the fight-or-flight hormones, and through it, immune suppression. Elevated levels of catecholamines, acting through 2-adrenergic receptors on precursor cells in erythroid differentiation, mis-direct erythroid differentiation causing accumulation of aberrant erythroid precursor cells (EPC) in mice as well as humans. EPC suppress priming as well as expansion of the CD8+ T cell response through their effect on dendritic cells (DC); EPC trogocytose cell surface MHC I from DC, and DC exposed to EPC are less effective at T cell activation. EPC suppress tumor immunity in several models and this suppression is exacerbated during adrenergic stress. The magnitude of suppression of tumor immunity by EPC is comparable to that mediated by regulatory T cells. Higher expression of CD71, a marker for EPC, is associated with poor overall and disease free survival in many human cancers. Our results uncover a role for adrenergic signaling in erythropoiesis, and establish erythroid cells, in addition to the lymphoid and myeloid cells, as significant determinants of cancer immunity.","manuscriptTitle":"Adrenergic stress misdirects erythropoiesis compromising cancer immunity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-13 03:08:42","doi":"10.21203/rs.3.rs-7435097/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-immunology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ni","sideBox":"Learn more about [Nature Immunology](http://www.nature.com/ni/)","snPcode":"","submissionUrl":"","title":"Nature Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4f065ab7-5434-410f-85cb-e58e3233fadb","owner":[],"postedDate":"October 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":55638279,"name":"Biological sciences/Immunology/Haematopoiesis/Erythropoiesis"},{"id":55638280,"name":"Health sciences/Medical research/Stem-cell research"}],"tags":[],"updatedAt":"2025-10-13T03:08:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-13 03:08:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7435097","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7435097","identity":"rs-7435097","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}