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One distinct feature of the CNS TIME is the limited infiltration and activation of dendritic cells (DCs). The impact of CNS versus non-CNS TIME can be assessed by injecting tumor cells from the same model, either subcutaneously (peripherally) or into the brain. Subcutaneous tumors drain into the tumor-draining lymph nodes in the skin (TdLN-p), whereas brain tumors drain into the deep cervical TdLN (TdLN-c). We previously showed that CNS tumors that are not responsive to immune checkpoint inhibition become responsive when grown peripherally, and that non-responsiveness correlates with a tolerogenic immune response in the local TIME and TdLN-c.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we investigated the immunoregulatory potential of cervical DCs (DC-c) compared with that of peripheral DCs (DC-p) using high-resolution flow cytometry, single-cell RNA sequencing, and ex vivo and in vivo functional characterization of TdLNs from mouse models of glioma and lymphoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our analysis revealed that DC-c promoted regulatory T-cell expansion and poorly cytotoxic CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells compared with DC-p. Furthermore, we identified OX40 (\n                      <jats:italic>Tnfrsf4<\/jats:italic>\n                      ) as a modulator of immunoregulatory DC-c function and found that its antitumor effect depended on lymphocyte trafficking and the DC transcription factor\n                      <jats:italic>Batf3<\/jats:italic>\n                      . CCR7+OX40+ DCs were efficient in antigen processing and presentation, and OX40 agonists further enhanced DC activation. In TIME, the CCR7+OX40+ DCs expressed OX40L, and blocking it promoted Treg formation ex vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings highlight the unique immunoregulatory functions of DC-c in TdLNs and suggest the importance of OX40 signaling through direct effects on CCR7+OX40+ DCs\u2009and indirect effects on T cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-011548","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T22:02:07Z","timestamp":1747864927000},"page":"e011548","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Brain tumors induce immunoregulatory dendritic cells in draining lymph nodes that can be targeted by OX40 agonist treatment"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3840-9448","authenticated-orcid":false,"given":"Oscar","family":"Badillo-Godinez","sequence":"first","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenni","family":"Niemi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Helfridsson","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shokoufeh","family":"Karimi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohanraj","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8460-4850","authenticated-orcid":false,"given":"Hitesh Bhagavanbhai","family":"Mangukiya","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Nelander","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats","family":"Hellstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"2026052723001985000_13.5.e011548.1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2020.00205","article-title":"Tumor-Specific T Cell Activation in Malignant Brain Tumors","volume":"11","author":"Mohme","year":"2020","journal-title":"Front Immunol"},{"key":"2026052723001985000_13.5.e011548.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0224-7"},{"key":"2026052723001985000_13.5.e011548.3","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/cam4.4438","article-title":"Treatment patterns and clinical outcomes for patients with melanoma and central nervous system metastases: A real-world study","volume":"11","author":"Tawbi","year":"2022","journal-title":"Cancer Med"},{"key":"2026052723001985000_13.5.e011548.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0488-6"},{"key":"2026052723001985000_13.5.e011548.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1805453"},{"key":"2026052723001985000_13.5.e011548.6","doi-asserted-by":"crossref","unstructured":"Hu X , Yu H , Zheng Y , et al . 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