{"paper_id":"494e1b01-fd2c-46ee-8f3c-1933082f4a9e","body_text":"MHC-II antigen presentation on cancer cells improves CD4+ T cell immunity and vaccine efficacy | 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 MHC-II antigen presentation on cancer cells improves CD4+ T cell immunity and vaccine efficacy Tyler Jacks, Sean-Luc Shanahan, Laura Maiorino, Jia-Yun Chen, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8264567/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 CD4+ T cells can be either protective or pathogenic in cancer [1-5], but how they interact with cancer cells to produce these effects remains poorly understood. Here, we developed a flexible autochthonous platform to introduce CD4+ T cell antigens in combination with CD8+ T cell antigens in a mouse lung cancer model. We found that tumor-specific CD4+ T cells potentiate CD8+ T cell control of tumor progression. Unlike previous studies emphasizing intratumoral interactions among dendritic cells, CD4+ T cells, and CD8+ T cells [4,5], we found that CD4+ T cell function and tumor control depend on direct antigen presentation by cancer cells via major histocompatibility complex class II (MHC-II). This direct interaction between cancer cells and CD4+ T cells led to increased immune infiltration, inflammatory remodeling, and sustained CD8+ T cell effector functions within tumors. Building on this, we demonstrate that tumor vaccination targeting both CD4+ and CD8+ T cell neoantigens significantly reduces tumor burden and requires cancer cell MHC-II presentation. These findings reveal an underappreciated mechanism of CD4+ T cell “help” and suggest a therapeutic approach targeting cancer cell presentation of MHC class II antigens. Biological sciences/Cancer/Tumour immunology Biological sciences/Cancer/Cancer models Biological sciences/Immunology/Adaptive immunity/Cellular immunity/Antigen presentation Biological sciences/Immunology/Antigen processing and presentation/MHC/MHC class II Biological sciences/Biotechnology/Applied immunology/Vaccines/RNA vaccines Full Text Additional Declarations Yes there is potential Competing Interest. Tyler Jacks is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, and a co-Founder of Dragonfly Therapeutics and T2 Biosystems. Tyler Jacks serves on the Scientific Advisory Board of Dragonfly Therapeutics and Skyhawk Therapeutics. Tyler Jacks is also the President of Break Through Cancer. His laboratory currently receives funding from The Lustgarten Foundation. Supplementary Files SupplementalTableStats.xlsx Dataset 1: Additional statistical information ShanahanetalSuppFigs120125.pdf Supplementary Figures 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-8264567\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Biological Sciences - Article\",\"associatedPublications\":[],\"authors\":[{\"id\":557571285,\"identity\":\"e44ff364-4a93-4881-8eb4-562c4b7aba71\",\"order_by\":0,\"name\":\"Tyler Jacks\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsUlEQVRIiWNgGAWjYFCCAwyMDQw2DGwgNg8xGnggWtIY2NiI18IA0nKYgYFoLfaMhx9+nPHnfDSffAPjg7dtRNlyzFhyY9vt3DY2BmbDucRpOWDG+LABrIVNmpc4Lce/MT74cw6khf03kVrOmDFuYDsAtoWZOC0HzhRLzmxLBmpJbJacc44ILewzjm/82PPHLnd+8+GDH96UEaGFQeIAjAWMHuIAP7EKR8EoGAWjYOQCADY+NfrnVtZ2AAAAAElFTkSuQmCC\",\"orcid\":\"https://orcid.org/0000-0001-5785-8911\",\"institution\":\"David H. 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