Nociceptor neurons impair cancer immunosurveillance

Nociceptor neurons impair cancer immunosurveillance | 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 Nociceptor neurons impair cancer immunosurveillance Sébastien Talbot, Mohammad Balood, Maryam Ahmadi, Tuany Eichwald, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-580730/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Nov, 2022 Read the published version in Nature → Version 1 posted You are reading this latest preprint version Abstract Solid tumors are innervated by nerve fibers that arise from the autonomic and sensory peripheral nervous systems. In prostate cancer, doublecortin-expressing neural progenitors initiate autonomic adrenergic neurogenesis1 which facilitates tumor development and dissemination2, via an angiogenic switch that fuels cancer growth3,4. Similarly, a loss of TP53 drives the reprogramming of tumor-innervating sensory nerves into adrenergic neurons in head and neck tumors, which promotes tumor growth5. However, the impact of tumor neo-innervation by pain-initiating sensory neurons remains unclear. We show that melanoma cells interact with nociceptors, increasing neurite outgrowth, responsiveness to noxious ligands, and neuropeptide release. In turn, CGRP, a nociceptor-produced neuropeptide, directly increases exhaustion of cytotoxic CD8+ T-cells (PD1+Lag3+Tim3+IFNγ-), limiting their capacity to eliminate melanoma. Genetic NaV1.8 or TRPV1 lineage ablation, local pharmacological silencing or blockade of neuropeptide release from tumor-innervating nociceptors, and the antagonism of the CGRP receptor RAMP1, all blunt tumor-infiltrating leukocyte exhaustion, and tumor growth, nearly tripling survival of B16F10-inoculated mice. Inversely, CD8+ T-cell exhaustion increased following optogenetic activation of tumor-innervating NaV1.8 neurons+ and was rescued in sensory neuron depleted mice treated with recombinant CGRP. In comparison to wild-type CD8+ T-cells, RAMP1-/- CD8+ T-cells were protected from undergoing exhaustion when co-transplanted into tumor-bearing Rag1 deficient mice. Single-cell RNA sequencing of patient tumors revealed that intratumoral RAMP1-expressing CD8+ T-cells are more exhausted than their RAMP1 negative counterparts. RAMP1 expression in intratumoral CD8+ T-cells was also associated with resistance to immune checkpoint inhibitor treatment, while RAMP1 overexpression within the tumor correlated with a worse clinical prognosis. We conclude that reducing CGRP release from tumor-innervating nociceptors, by eliminating its immunomodulatory action on cytotoxic CD8+ T-cells, constitutes a useful strategy to safeguard anti-tumor immunity. Cancer Biology Immunology Nociceptor neurons neuro-immunology tumor innervation melanoma exhaustion cytotoxic CD8+ T-cells CGRP TRPV1 QX-314 Botox. Full Text Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the manuscript can be downloaded and accessed as a PDF. Additional Declarations Yes there is potential Competing Interest. ST and CJW hold an equity stake in Nocion Therapeutics Cite Share Download PDF Status: Published Journal Publication published 02 Nov, 2022 Read the published version in Nature → 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-580730","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":31695461,"identity":"dc258cfd-f541-46f2-96be-4731ebcb4d75","order_by":0,"name":"Sébastien 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Kirby Neurobiology Research Center, Boston Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Clifford","middleName":"","lastName":"Woolf","suffix":""}],"badges":[],"createdAt":"2021-06-01 18:01:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-580730/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-580730/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41586-022-05374-w","type":"published","date":"2022-11-02T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":28594388,"identity":"e568c626-1883-4495-9e41-c94e42c398ec","added_by":"auto","created_at":"2022-11-03 07:07:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":58901746,"visible":true,"origin":"","legend":"","description":"","filename":"Balood.Nature.2021.pdf","url":"https://assets-eu.researchsquare.com/files/rs-580730/v1_covered.pdf"},{"id":13642460,"identity":"e86d9616-e11c-42f7-9861-2e3320139f46","added_by":"auto","created_at":"2021-09-17 09:07:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":58897004,"visible":true,"origin":"","legend":"","description":"","filename":"Balood.Nature.2021.pdf","url":"https://assets-eu.researchsquare.com/files/rs-580730/v1_covered.pdf"},{"id":10163100,"identity":"3584e07b-b9c3-4fcc-aafc-94abdd14530d","added_by":"auto","created_at":"2021-06-09 15:05:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":58893465,"visible":true,"origin":"","legend":"","description":"","filename":"Balood.Nature.2021.pdf","url":"https://assets-eu.researchsquare.com/files/rs-580730/v1_covered.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nST and CJW hold an equity stake in Nocion Therapeutics","formattedTitle":"Nociceptor neurons impair cancer immunosurveillance","fulltext":[{"header":"Full Text","content":"\u003cp\u003eDue to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the manuscript can be downloaded and accessed as a PDF.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Nociceptor neurons, neuro-immunology, tumor innervation, melanoma, exhaustion, cytotoxic CD8+ T-cells, CGRP, TRPV1, QX-314, Botox.","lastPublishedDoi":"10.21203/rs.3.rs-580730/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-580730/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Solid tumors are innervated by nerve fibers that arise from the autonomic and sensory peripheral nervous systems. In prostate cancer, doublecortin-expressing neural progenitors initiate autonomic adrenergic neurogenesis1 which facilitates tumor development and dissemination2, via an angiogenic switch that fuels cancer growth3,4. Similarly, a loss of TP53 drives the reprogramming of tumor-innervating sensory nerves into adrenergic neurons in head and neck tumors, which promotes tumor growth5. However, the impact of tumor neo-innervation by pain-initiating sensory neurons remains unclear. We show that melanoma cells interact with nociceptors, increasing neurite outgrowth, responsiveness to noxious ligands, and neuropeptide release. In turn, CGRP, a nociceptor-produced neuropeptide, directly increases exhaustion of cytotoxic CD8+ T-cells (PD1+Lag3+Tim3+IFNγ-), limiting their capacity to eliminate melanoma. Genetic NaV1.8 or TRPV1 lineage ablation, local pharmacological silencing or blockade of neuropeptide release from tumor-innervating nociceptors, and the antagonism of the CGRP receptor RAMP1, all blunt tumor-infiltrating leukocyte exhaustion, and tumor growth, nearly tripling survival of B16F10-inoculated mice. Inversely, CD8+ T-cell exhaustion increased following optogenetic activation of tumor-innervating NaV1.8 neurons+ and was rescued in sensory neuron depleted mice treated with recombinant CGRP. In comparison to wild-type CD8+ T-cells, RAMP1-/- CD8+ T-cells were protected from undergoing exhaustion when co-transplanted into tumor-bearing Rag1 deficient mice. Single-cell RNA sequencing of patient tumors revealed that intratumoral RAMP1-expressing CD8+ T-cells are more exhausted than their RAMP1 negative counterparts. RAMP1 expression in intratumoral CD8+ T-cells was also associated with resistance to immune checkpoint inhibitor treatment, while RAMP1 overexpression within the tumor correlated with a worse clinical prognosis. We conclude that reducing CGRP release from tumor-innervating nociceptors, by eliminating its immunomodulatory action on cytotoxic CD8+ T-cells, constitutes a useful strategy to safeguard anti-tumor immunity.","manuscriptTitle":"Nociceptor neurons impair cancer immunosurveillance","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-06-09 15:03:56","doi":"10.21203/rs.3.rs-580730/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"2067699c-becb-41c1-a7c1-46d3b07a3433","owner":[],"postedDate":"June 9th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":4888564,"name":"Cancer Biology"},{"id":4888565,"name":"Immunology"}],"tags":[],"updatedAt":"2022-11-03T07:06:10+00:00","versionOfRecord":{"articleIdentity":"rs-580730","link":"https://doi.org/10.1038/s41586-022-05374-w","journal":{"identity":"nature","isVorOnly":false,"title":"Nature"},"publishedOn":"2022-11-02 04:00:00","publishedOnDateReadable":"November 2nd, 2022"},"versionCreatedAt":"2021-06-09 15:03:56","video":"","vorDoi":"10.1038/s41586-022-05374-w","vorDoiUrl":"https://doi.org/10.1038/s41586-022-05374-w","workflowStages":[]},"version":"v1","identity":"rs-580730","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-580730","identity":"rs-580730","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}