{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T14:19:51Z","timestamp":1792592391755,"version":"4.5.0"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T00:00:00Z","timestamp":1722384000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T00:00:00Z","timestamp":1722384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The ecosystem of brain tumors is considered immunosuppressed, but our current knowledge may be incomplete. Here we analyzed clinical cell and tissue specimens derived from patients presenting with glioblastoma or nonmalignant intracranial disease to report that the cranial bone (CB) marrow, in juxtaposition to treatment-naive glioblastoma tumors, harbors active lymphoid populations at the time of initial diagnosis. Clinical and anatomical imaging, single-cell molecular and immune cell profiling and quantification of tumor reactivity identified CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell clonotypes in the CB that were also found in the tumor. These were characterized by acute and durable antitumor response rooted in the entire T cell developmental spectrum. In contrast to distal bone marrow, the CB niche proximal to the tumor showed increased frequencies of tumor-reactive CD8\n                    <jats:sup>+<\/jats:sup>\n                    effector types expressing the lymphoid egress marker S1PR1. In line with this, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker indicating focal association with improved progression-free survival. The data of this study advocate preservation and further exploitation of these cranioencephalic units for the clinical care of glioblastoma.\n                  <\/jats:p>","DOI":"10.1038\/s41591-024-03152-x","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T06:02:47Z","timestamp":1722405767000},"page":"2947-2956","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Cranioencephalic functional lymphoid units in glioblastoma"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4233-102X","authenticated-orcid":false,"given":"Celia","family":"Dobersalske","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8348-4298","authenticated-orcid":false,"given":"Laur\u00e8l","family":"Rauschenbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1695-172X","authenticated-orcid":false,"given":"Yichao","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9201-8803","authenticated-orcid":false,"given":"Christoph","family":"Berliner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Steinbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7928-5613","authenticated-orcid":false,"given":"Anika","family":"Gr\u00fcneboom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos D.","family":"Kokkaliaris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9258-3033","authenticated-orcid":false,"given":"Dieter H.","family":"Heiland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1453-3193","authenticated-orcid":false,"given":"Pia","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0286-7233","authenticated-orcid":false,"given":"Sarah","family":"Langer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2529-1030","authenticated-orcid":false,"given":"Chin L.","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Stenzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somaya","family":"Landolsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6407-8542","authenticated-orcid":false,"given":"Flora","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Darkwah Oppong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf A.","family":"Werner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanah","family":"Gull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Schr\u00f6der","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6763-8680","authenticated-orcid":false,"given":"Thomas","family":"Linsenmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas K.","family":"Buck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5534-6055","authenticated-orcid":false,"given":"Matthias","family":"Gunzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Stuschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2558-5159","authenticated-orcid":false,"given":"Kathy","family":"Keyvani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Forsting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Glas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3714-517X","authenticated-orcid":false,"given":"Jonathan","family":"Kipnis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis A.","family":"Steindler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans Christian","family":"Reinhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1922-2298","authenticated-orcid":false,"given":"Edward W.","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4746-887X","authenticated-orcid":false,"given":"Michael","family":"Platten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2543-852X","authenticated-orcid":false,"given":"Alpaslan","family":"Tasdogan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Herrmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Rambow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Cima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9073-1821","authenticated-orcid":false,"given":"Ulrich","family":"Sure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8316-6556","authenticated-orcid":false,"given":"Bj\u00f6rn","family":"Scheffler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,31]]},"reference":[{"key":"3152_CR1","doi-asserted-by":"crossref","first-page":"eabo7649","DOI":"10.1126\/science.abo7649","volume":"380","author":"G Castellani","year":"2023","unstructured":"Castellani, G., Croese, T., Peralta Ramos, J. M. & Schwartz, M. Transforming the understanding of brain immunity. Science 380, eabo7649 (2023).","journal-title":"Science"},{"key":"3152_CR2","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.cell.2020.12.040","volume":"184","author":"J Rustenhoven","year":"2021","unstructured":"Rustenhoven, J. et al. Functional characterization of the dural sinuses as a neuroimmune interface. Cell 184, 1000\u20131016 (2021).","journal-title":"Cell"},{"key":"3152_CR3","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1126\/science.adc8810","volume":"379","author":"K Mollgard","year":"2023","unstructured":"Mollgard, K. et al. A mesothelium divides the subarachnoid space into functional compartments. Science 379, 84\u201388 (2023).","journal-title":"Science"},{"key":"3152_CR4","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/s41591-023-02673-1","volume":"30","author":"R Sankowski","year":"2024","unstructured":"Sankowski, R. et al. Multiomic spatial landscape of innate immune cells at human central nervous system borders. Nat. Med. 30, 186\u2013198 (2024).","journal-title":"Nat. Med."},{"key":"3152_CR5","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature14432","volume":"523","author":"A Louveau","year":"2015","unstructured":"Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337\u2013341 (2015).","journal-title":"Nature"},{"key":"3152_CR6","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41586-023-06993-7","volume":"627","author":"LCD Smyth","year":"2024","unstructured":"Smyth, L. C. D. et al. Identification of direct connections between the dura and the brain. Nature 627, 165\u2013173 (2024).","journal-title":"Nature"},{"key":"3152_CR7","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1038\/s41593-023-01487-1","volume":"26","author":"JA Mazzitelli","year":"2023","unstructured":"Mazzitelli, J. A. et al. Skull bone marrow channels as immune gateways to the central nervous system. Nat. Neurosci. 26, 2052\u20132062 (2023).","journal-title":"Nat. Neurosci."},{"key":"3152_CR8","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1093\/neuonc\/noaa106","volume":"22","author":"PY Wen","year":"2020","unstructured":"Wen, P. Y. et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol. 22, 1073\u20131113 (2020).","journal-title":"Neuro Oncol."},{"key":"3152_CR9","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/s41590-019-0433-y","volume":"20","author":"CM Jackson","year":"2019","unstructured":"Jackson, C. M., Choi, J. & Lim, M. Mechanisms of immunotherapy resistance: lessons from glioblastoma. Nat. Immunol. 20, 1100\u20131109 (2019).","journal-title":"Nat. Immunol."},{"key":"3152_CR10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/s41568-019-0224-7","volume":"20","author":"JH Sampson","year":"2020","unstructured":"Sampson, J. H., Gunn, M. D., Fecci, P. E. & Ashley, D. M. Brain immunology and immunotherapy in brain tumours. Nat. Rev. Cancer 20, 12\u201325 (2020).","journal-title":"Nat. Rev. Cancer"},{"key":"3152_CR11","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1038\/s41591-018-0135-2","volume":"24","author":"P Chongsathidkiet","year":"2018","unstructured":"Chongsathidkiet, P. et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat. Med. 24, 1459\u20131468 (2018).","journal-title":"Nat. Med."},{"key":"3152_CR12","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41580-019-0103-9","volume":"20","author":"S Pinho","year":"2019","unstructured":"Pinho, S. & Frenette, P. S. Haematopoietic stem cell activity and interactions with the niche. Nat. Rev. Mol. Cell Biol. 20, 303\u2013320 (2019).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"3152_CR13","doi-asserted-by":"crossref","first-page":"4133","DOI":"10.1007\/s00259-022-05849-y","volume":"49","author":"AK Buck","year":"2022","unstructured":"Buck, A. K. et al. CXCR4-targeted theranostics in oncology. Eur. J. Nucl. Med. Mol. Imaging 49, 4133\u20134144 (2022).","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"3152_CR14","doi-asserted-by":"crossref","first-page":"428","DOI":"10.7150\/thno.13986","volume":"6","author":"C Lapa","year":"2016","unstructured":"Lapa, C. et al. 68Ga-Pentixafor-PET\/CT for imaging of chemokine receptor 4 expression in glioblastoma. Theranostics 6, 428\u2013434 (2016).","journal-title":"Theranostics"},{"key":"3152_CR15","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/s42255-018-0016-5","volume":"1","author":"A Gruneboom","year":"2019","unstructured":"Gruneboom, A. et al. A network of trans-cortical capillaries as mainstay for blood circulation in long bones. Nat. Metab. 1, 236\u2013250 (2019).","journal-title":"Nat. Metab."},{"key":"3152_CR16","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1016\/j.cell.2020.04.055","volume":"181","author":"E Friebel","year":"2020","unstructured":"Friebel, E. et al. Single-cell mapping of human brain cancer reveals tumor-specific instruction of tissue-invading leukocytes. Cell 181, 1626\u20131642 (2020).","journal-title":"Cell"},{"key":"3152_CR17","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1016\/j.cell.2020.05.007","volume":"181","author":"F Klemm","year":"2020","unstructured":"Klemm, F. et al. Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell 181, 1643\u20131660 (2020).","journal-title":"Cell"},{"key":"3152_CR18","volume":"12","author":"IN Lu","year":"2021","unstructured":"Lu, I. N. et al. Tumor-associated hematopoietic stem and progenitor cells positively linked to glioblastoma progression. Nat. Commun. 12, 3895 (2021).","journal-title":"Nat. Commun."},{"key":"3152_CR19","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/s41590-022-01215-0","volume":"23","author":"AT Yeo","year":"2022","unstructured":"Yeo, A. T. et al. Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression. Nat. Immunol. 23, 971\u2013984 (2022).","journal-title":"Nat. Immunol."},{"key":"3152_CR20","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/s41593-020-00789-y","volume":"24","author":"AR Pombo Antunes","year":"2021","unstructured":"Pombo Antunes, A. R. et al. Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization. Nat. Neurosci. 24, 595\u2013610 (2021).","journal-title":"Nat. Neurosci."},{"key":"3152_CR21","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.cmet.2023.11.013","volume":"36","author":"A Rashidi","year":"2024","unstructured":"Rashidi, A. et al. Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth. Cell Metab. 36, 62\u201377 (2024).","journal-title":"Cell Metab."},{"key":"3152_CR22","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1038\/nm914","volume":"9","author":"M Feuerer","year":"2003","unstructured":"Feuerer, M. et al. Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat. Med. 9, 1151\u20131157 (2003).","journal-title":"Nat. Med."},{"key":"3152_CR23","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/s41568-023-00615-0","volume":"23","author":"T Gebhardt","year":"2023","unstructured":"Gebhardt, T., Park, S. L. & Parish, I. A. Stem-like exhausted and memory CD8+ T cells in cancer. Nat. Rev. Cancer 23, 780\u2013798 (2023).","journal-title":"Nat. Rev. Cancer"},{"key":"3152_CR24","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41587-019-0068-4","volume":"37","author":"M Setty","year":"2019","unstructured":"Setty, M. et al. Characterization of cell fate probabilities in single-cell data with Palantir. Nat. Biotechnol. 37, 451\u2013460 (2019).","journal-title":"Nat. Biotechnol."},{"key":"3152_CR25","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1126\/science.aax0249","volume":"367","author":"GS Gulati","year":"2020","unstructured":"Gulati, G. S. et al. Single-cell transcriptional diversity is a hallmark of developmental potential. Science 367, 405\u2013411 (2020).","journal-title":"Science"},{"key":"3152_CR26","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1016\/j.stem.2021.04.027","volume":"28","author":"D Meistermann","year":"2021","unstructured":"Meistermann, D. et al. Integrated pseudotime analysis of human pre-implantation embryo single-cell transcriptomes reveals the dynamics of lineage specification. Cell Stem Cell 28, 1625\u20131640 (2021).","journal-title":"Cell Stem Cell"},{"key":"3152_CR27","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1038\/s41591-023-02371-y","volume":"29","author":"Y Chu","year":"2023","unstructured":"Chu, Y. et al. Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat. Med. 29, 1550\u20131562 (2023).","journal-title":"Nat. Med."},{"key":"3152_CR28","doi-asserted-by":"crossref","unstructured":"Stress response in tumor-infiltrating T cells is linked to immunotherapy resistance. Nat. Med. 29, 1336\u20131337 (2023).","DOI":"10.1038\/s41591-023-02370-z"},{"key":"3152_CR29","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41568-019-0144-6","volume":"19","author":"C Sautes-Fridman","year":"2019","unstructured":"Sautes-Fridman, C., Petitprez, F., Calderaro, J. & Fridman, W. H. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat. Rev. Cancer 19, 307\u2013325 (2019).","journal-title":"Nat. Rev. Cancer"},{"key":"3152_CR30","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.cell.2019.07.049","volume":"178","author":"N Collins","year":"2019","unstructured":"Collins, N. et al. The bone marrow protects and optimizes immunological memory during dietary restriction. Cell 178, 1088\u20131101 (2019).","journal-title":"Cell"},{"key":"3152_CR31","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/nri2974","volume":"11","author":"S Spiegel","year":"2011","unstructured":"Spiegel, S. & Milstien, S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat. Rev. Immunol. 11, 403\u2013415 (2011).","journal-title":"Nat. Rev. Immunol."},{"key":"3152_CR32","doi-asserted-by":"publisher","unstructured":"Tan, C. L. et al. Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy. Nat. Biotechnol. https:\/\/doi.org\/10.1038\/s41587-024-02161-y (2024).","DOI":"10.1038\/s41587-024-02161-y"},{"key":"3152_CR33","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/s43018-023-00706-9","volume":"5","author":"A Upadhye","year":"2024","unstructured":"Upadhye, A. et al. Intra-tumoral T cells in pediatric brain tumors display clonal expansion and effector properties. Nat. Cancer 5, 791\u2013807 (2024).","journal-title":"Nat. Cancer"},{"key":"3152_CR34","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1056\/NEJMoa051424","volume":"353","author":"F Pages","year":"2005","unstructured":"Pages, F. et al. Effector memory T cells, early metastasis and survival in colorectal cancer. N. Engl. J. Med. 353, 2654\u20132666 (2005).","journal-title":"N. Engl. J. Med."},{"key":"3152_CR35","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41591-019-0734-6","volume":"26","author":"BP Fairfax","year":"2020","unstructured":"Fairfax, B. P. et al. Peripheral CD8+ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma. Nat. Med. 26, 193\u2013199 (2020).","journal-title":"Nat. Med."},{"key":"3152_CR36","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.immuni.2005.01.008","volume":"22","author":"IB Mazo","year":"2005","unstructured":"Mazo, I. B. et al. Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity 22, 259\u2013270 (2005).","journal-title":"Immunity"},{"key":"3152_CR37","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41586-019-1912-x","volume":"577","author":"E Song","year":"2020","unstructured":"Song, E. et al. VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature 577, 689\u2013694 (2020).","journal-title":"Nature"},{"key":"3152_CR38","volume":"3","author":"J Blobner","year":"2021","unstructured":"Blobner, J. et al. Comparative evaluation of T-cell receptors in experimental glioma-draining lymph nodes. Neurooncol. Adv. 3, vdab147 (2021).","journal-title":"Neurooncol. Adv."},{"key":"3152_CR39","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s11060-021-03822-7","volume":"154","author":"B Noffsinger","year":"2021","unstructured":"Noffsinger, B. et al. Technical choices significantly alter the adaptive immune response against immunocompetent murine gliomas in a model-dependent manner. J. Neurooncol. 154, 145\u2013157 (2021).","journal-title":"J. Neurooncol."},{"key":"3152_CR40","doi-asserted-by":"crossref","first-page":"abe6474","DOI":"10.1126\/science.abe6474","volume":"374","author":"L Zheng","year":"2021","unstructured":"Zheng, L. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474 (2021).","journal-title":"Science"},{"key":"3152_CR41","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s43018-023-00566-3","volume":"4","author":"V Wischnewski","year":"2023","unstructured":"Wischnewski, V. et al. Phenotypic diversity of T cells in human primary and metastatic brain tumors revealed by multiomic interrogation. Nat. Cancer 4, 908\u2013924 (2023).","journal-title":"Nat. Cancer"},{"key":"3152_CR42","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/s41571-020-0347-5","volume":"17","author":"ME Goebeler","year":"2020","unstructured":"Goebeler, M. E. & Bargou, R. C. T cell-engaging therapies\u2014BiTEs and beyond. Nat. Rev. Clin. Oncol. 17, 418\u2013434 (2020).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"3152_CR43","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1038\/s41591-024-02893-z","volume":"30","author":"SJ Bagley","year":"2024","unstructured":"Bagley, S. J. et al. Intrathecal bivalent CAR T cells targeting EGFR and IL13R\u03b12 in recurrent glioblastoma: phase 1 trial interim results. Nat. Med. 30, 1320\u20131329 (2024).","journal-title":"Nat. Med."},{"key":"3152_CR44","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/s41591-024-02875-1","volume":"30","author":"CE Brown","year":"2024","unstructured":"Brown, C. E. et al. Locoregional delivery of IL-13R\u03b12-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat. Med. 30, 1001\u20131012 (2024).","journal-title":"Nat. Med."},{"key":"3152_CR45","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1056\/NEJMoa2314390","volume":"390","author":"BD Choi","year":"2024","unstructured":"Choi, B. D. et al. Intraventricular CARv3-TEAM-E T cells in recurrent glioblastoma. N. Engl. J. Med. 390, 1290\u20131298 (2024).","journal-title":"N. Engl. J. Med."},{"key":"3152_CR46","doi-asserted-by":"crossref","first-page":"104963","DOI":"10.1016\/j.ebiom.2023.104963","volume":"100","author":"Z Xiong","year":"2024","unstructured":"Xiong, Z. et al. Glioblastoma vaccines: past, present and opportunities. EBioMedicine 100, 104963 (2024).","journal-title":"EBioMedicine"},{"key":"3152_CR47","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/s41591-018-0337-7","volume":"25","author":"TF Cloughesy","year":"2019","unstructured":"Cloughesy, T. F. et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat. Med. 25, 477\u2013486 (2019).","journal-title":"Nat. Med."},{"key":"3152_CR48","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/s41591-018-0339-5","volume":"25","author":"KA Schalper","year":"2019","unstructured":"Schalper, K. A. et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat. Med. 25, 470\u2013476 (2019).","journal-title":"Nat. Med."},{"key":"3152_CR49","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1093\/neuonc\/nov029","volume":"17","author":"AL Stensjoen","year":"2015","unstructured":"Stensjoen, A. L. et al. Growth dynamics of untreated glioblastomas in vivo. Neuro Oncol 17, 1402\u20131411 (2015).","journal-title":"Neuro Oncol"},{"key":"3152_CR50","unstructured":"WHO Classification of Tumors Editorial Board. Central Nervous System Tumours: WHO Classification of Tumours, Fifth Edition Vol. 6 (International Agency for Research on Cancer, 2021)."},{"key":"3152_CR51","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1002\/ana.22036","volume":"68","author":"M Glas","year":"2010","unstructured":"Glas, M. et al. Residual tumor cells are unique cellular targets in glioblastoma. Ann. Neurol. 68, 264\u2013269 (2010).","journal-title":"Ann. Neurol."},{"key":"3152_CR52","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","volume":"184","author":"Y Hao","year":"2021","unstructured":"Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573\u20133587 (2021).","journal-title":"Cell"},{"key":"3152_CR53","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.cels.2019.03.003","volume":"8","author":"CS McGinnis","year":"2019","unstructured":"McGinnis, C. S., Murrow, L. M. & Gartner, Z. J. DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst. 8, 329\u2013337.e4 (2019).","journal-title":"Cell Syst."},{"key":"3152_CR54","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","volume":"16","author":"I Korsunsky","year":"2019","unstructured":"Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289\u20131296 (2019).","journal-title":"Nat. Methods"},{"key":"3152_CR55","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","volume":"20","author":"D Aran","year":"2019","unstructured":"Aran, D. et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat. Immunol. 20, 163\u2013172 (2019).","journal-title":"Nat. Immunol."},{"key":"3152_CR56","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/nmeth.4463","volume":"14","author":"S Aibar","year":"2017","unstructured":"Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083\u20131086 (2017).","journal-title":"Nat. Methods"},{"key":"3152_CR57","doi-asserted-by":"publisher","unstructured":"Ruiz-Moreno, C. et al. Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2022.08.27.505439 (2022).","DOI":"10.1101\/2022.08.27.505439"},{"key":"3152_CR58","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1038\/s41587-019-0336-3","volume":"37","author":"KR Moon","year":"2019","unstructured":"Moon, K. R. et al. Visualizing structure and transitions in high-dimensional biological data. Nat. Biotechnol. 37, 1482\u20131492 (2019).","journal-title":"Nat. Biotechnol."},{"key":"3152_CR59","doi-asserted-by":"crossref","first-page":"47","DOI":"10.12688\/f1000research.22139.1","volume":"9","author":"N Borcherding","year":"2020","unstructured":"Borcherding, N., Bormann, N. L. & Kraus, G. scRepertoire: an R-based toolkit for single-cell immune receptor analysis. F1000Res 9, 47 (2020).","journal-title":"F1000Res"},{"key":"3152_CR60","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nbt.2859","volume":"32","author":"C Trapnell","year":"2014","unstructured":"Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381\u2013386 (2014).","journal-title":"Nat. Biotechnol."},{"key":"3152_CR61","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1016\/j.ccell.2022.11.002","volume":"40","author":"Y Hua","year":"2022","unstructured":"Hua, Y. et al. Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop. Cancer Cell 40, 1600\u20131618 (2022).","journal-title":"Cancer Cell"},{"key":"3152_CR62","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.cels.2019.06.004","volume":"9","author":"Y Tan","year":"2019","unstructured":"Tan, Y. & Cahan, P. SingleCellNet: a computational tool to classify single cell RNA-seq data across platforms and across species. Cell Syst. 9, 207\u2013213 (2019).","journal-title":"Cell Syst."},{"key":"3152_CR63","doi-asserted-by":"crossref","first-page":"e1252894","DOI":"10.1080\/2162402X.2016.1252894","volume":"6","author":"Z Liu","year":"2017","unstructured":"Liu, Z. et al. Tumor-infiltrating lymphocytes (TILs) from patients with glioma. Oncoimmunology 6, e1252894 (2017).","journal-title":"Oncoimmunology"},{"key":"3152_CR64","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.3389\/fimmu.2018.02084","volume":"9","author":"A Yanguas","year":"2018","unstructured":"Yanguas, A. et al. ICAM-1-LFA-1 dependent CD8+ T-lymphocyte aggregation in tumor tissue prevents recirculation to draining lymph nodes. Front. Immunol. 9, 2084 (2018).","journal-title":"Front. Immunol."},{"key":"3152_CR65","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.cell.2018.07.009","volume":"174","author":"KK Dijkstra","year":"2018","unstructured":"Dijkstra, K. K. et al. Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 174, 1586\u20131598 (2018).","journal-title":"Cell"},{"key":"3152_CR66","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41596-019-0232-9","volume":"15","author":"CM Cattaneo","year":"2020","unstructured":"Cattaneo, C. M. et al. Tumor organoid-T-cell coculture systems. Nat. Protoc. 15, 15\u201339 (2020).","journal-title":"Nat. Protoc."},{"key":"3152_CR67","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1038\/s41591-021-01404-8","volume":"27","author":"NA Vitanza","year":"2021","unstructured":"Vitanza, N. A. et al. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. Nat. Med. 27, 1544\u20131552 (2021).","journal-title":"Nat. Med."},{"key":"3152_CR68","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1038\/s41591-022-01897-x","volume":"28","author":"T Todo","year":"2022","unstructured":"Todo, T. et al. Intratumoral oncolytic herpes virus G47\u2206 for residual or recurrent glioblastoma: a phase 2 trial. Nat. Med. 28, 1630\u20131639 (2022).","journal-title":"Nat. Med."},{"key":"3152_CR69","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1038\/s41591-023-02347-y","volume":"29","author":"F Nassiri","year":"2023","unstructured":"Nassiri, F. et al. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1\/2 trial. Nat. Med. 29, 1370\u20131378 (2023).","journal-title":"Nat. Med."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03152-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03152-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03152-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T18:07:37Z","timestamp":1729102057000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03152-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,31]]},"references-count":69,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["3152"],"URL":"https:\/\/doi.org\/10.1038\/s41591-024-03152-x","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,31]]},"assertion":[{"value":"26 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 June 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 July 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"C.D., L.R., D.A.S., F.R., I.C., U.S. and B.S. are inventors on a patent application related to cellular data of this study (EP24160641.7). C.L.T., M.P. and E.W.G. are inventors on a patent application describing the identification of tumor-reactive TCRs (WO 2022\/200456). M.D.O. receives consulting fees from Brainlab AG and no support was provided for this study or data presented here. D.A.S. is a cofounder of Round Table Research, focused on oncology and degenerative diseases, with currently unrelated technologies and no support provided for this study or data presented here. R.A.W. has received speaker honoraria from Novartis\/AAA and PentixaPharm, reports advisory board work for Novartis\/AAA and Bayer and is involved in <sup>68<\/sup>Ga-Pentixafor PET Imaging in PAN Cancer (FORPAN; sponsored and planned by PentixaPharm). A.K.B. has received speaker honoraria from Novartis\/AAA and PentixaPharm, is a board member\/officer\/trustee for PentixaPharm and is involved in <sup>68<\/sup>Ga-Pentixafor PET Imaging in PAN Cancer (FORPAN; sponsored and planned by PentixaPharm). H.C.R. received consulting and lecture fees from AbbVie, AstraZeneca, Roche, Janssen-Cilag, Novartis, Vertex and Merck; has received research funding from Gilead and AstraZeneca; and is a cofounder of CDL Therapeutics GmbH. M.P. and E.W.G. are founders of Tcelltech GmbH. B.S. reports grants from BMWK and DKFZ-Bayer Joint Alliance outside the submitted work. Additionally, B.S. has a patent for peripheral zone tumor cells, methods for their preparation and use issued (EP2324111, AU 2009291203 and USPTO 9,103,819). The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}