{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T15:29:00Z","timestamp":1781018940044,"version":"3.54.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Tissue biomarkers that aid in identifying cutaneous melanoma (CM) patients who will benefit from adjuvant immunotherapy are of crucial interest. Metastatic tumor-draining lymph nodes (mTDLN) are the first encounter site between the metastatic CM cells and an organized immune structure. Therefore, their study may reveal mechanisms that could influence patients\u00b4 outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty-nine stage-III CM patients enrolled in clinical trials to study the vaccine VACCIMEL were included in this retrospective study. After radical mTDLN dissection, patients were treated with VACCIMEL (n=22) or IFN\u03b1-2b (n=6), unless rapid progression (n=1). Distant Metastasis-Free Survival (DMFS) was selected as an end-point. Two cohorts of patients were selected: one with a good outcome (GO) (n=17; median DMFS 130.0 months), and another with a bad outcome (BO) (n=12; median DMFS 8.5 months). We analyzed by immunohistochemistry and immunofluorescence the expression of relevant biomarkers to tumor-cell biology and immune cells and structures in mTDLN, both in the tumor and peritumoral areas.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In BO patients, highly replicating Ki-67<jats:sup>+<\/jats:sup> tumor cells, low tumor HLA-I expression and abundant FoxP3<jats:sup>+<\/jats:sup> lymphocytes were found (<jats:italic>p=0.037; p=0.056<\/jats:italic> and <jats:italic>p=0.021<\/jats:italic>). In GO patients, the most favorable biomarkers for prolonged DMFS were the abundance of peri- and intra-tumoral CD11c<jats:sup>+<\/jats:sup> cells (<jats:italic>p=0.0002<\/jats:italic> and <jats:italic>p=0.001<\/jats:italic>), peri-tumoral DC-LAMP<jats:sup>+<\/jats:sup> dendritic cells (DCs) (<jats:italic>p=0.001<\/jats:italic>), and PNAd<jats:sup>+<\/jats:sup> High Endothelial Venules (HEVs) (<jats:italic>p=0.004<\/jats:italic>). Most strikingly, we describe in GO patients a peculiar, heterogeneous structure that we named FAPS (Favoring Antigen-Presenting Structure), a triad composed of DC, HEV and CD62L<jats:sup>+<\/jats:sup> na\u00efve lymphocytes, whose postulated role would be to favor tumor antigen (Ag) priming of incoming na\u00efve lymphocytes. We also found in GO patients a preferential tumor infiltration of CD8<jats:sup>+<\/jats:sup> and CD20<jats:sup>+<\/jats:sup> lymphocytes (<jats:italic>p=0.004<\/jats:italic> and <jats:italic>p=0.027<\/jats:italic>), as well as peritumoral CD20<jats:sup>+<\/jats:sup> aggregates, with no CD21<jats:sup>+<\/jats:sup> follicular dendritic cells detected (<jats:italic>p=0.023<\/jats:italic>). Heterogeneous infiltration with CD64<jats:sup>+<\/jats:sup>CD68<jats:sup>-<\/jats:sup>CD163<jats:sup>-<\/jats:sup>, CD64<jats:sup>+<\/jats:sup>CD68<jats:sup>+<\/jats:sup>CD163<jats:sup>-<\/jats:sup> and CD64<jats:sup>+<\/jats:sup>CD68<jats:sup>+<\/jats:sup>CD163<jats:sup>+<\/jats:sup> macrophages were observed in both cohorts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The analysis of mTDLN in GO and BO patients revealed marked differences. This work highlights the importance of analyzing resected mTDLN from CM patients and suggests a correlation between tumor and immune characteristics that may be associated with a spontaneous or vaccine-induced long DMFS. These results should be confirmed in prospective studies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1231734","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T17:48:10Z","timestamp":1692985690000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["HEV-associated dendritic cells are observed in metastatic tumor-draining lymph nodes of cutaneous melanoma patients with longer distant metastasis-free survival after adjuvant immunotherapy"],"prefix":"10.3389","volume":"14","author":[{"given":"Alicia 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