Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node

Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node | 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 Article Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node Zachary Buchwald, Yang Shen, Erin Connolly, Meili Aiello, Chengjing Zhou, and 21 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3921977/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Apr, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a CD8+ PD-1+ Tcf-1+ stem-like T cell subset in the tumor-draining lymph node (TdLN). Using murine melanoma models, we found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. Our data indicate that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor. Biological sciences/Cancer/Tumour immunology Biological sciences/Cancer/Cancer therapy Biological sciences/Immunology/Tumour immunology Radiation immunotherapy PD-1 PD-L1 checkpoint blockade stem-like T cells Tcf-1 tumor- draining lymph node abscopal effect Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations Yes there is potential Competing Interest. N.C.S. has a consulting role at Checkpoint Surgical, Sensorion, and Synergy Research, Inc, is a member of the advisory board of Regeneron, receives book royalties from Plural Publishing, and has received funding from Astex Pharmaceuticals. GBL has received research funding through a sponsored research agreement between Emory University and Merck and Co., Bristol-Myers Squibb, Boerhinger-Ingelheim, and Vaccinex. All studies were reviewed and approved by the institutional IACUC committee. The IACUC institution was Emory University School of Medicine. Supplementary Files KeyResourcesTable.docx Key Resources Table Supplementalfigures.pdf Supplemental figures SupplementaryTable1.csv SupplementaryTable2.xls Cite Share Download PDF Status: Published Journal Publication published 14 Apr, 2025 Read the published version in Nature Communications → 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-3921977","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":272880097,"identity":"2fd8e3c8-e768-4532-a82b-b42a71b956ae","order_by":0,"name":"Zachary 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