{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:39:15Z","timestamp":1787020755934,"version":"build-2736575974"},"reference-count":75,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003252","name":"Lund University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003252","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Metastasis to lymph nodes is strongly associated with reduced survival in breast cancer patients. To increase the understanding on how lymph node metastasis impairs the local immune response in affected lymph nodes, we here studied spatial proteomic changes of critical lymph node immune populations in uninvolved lymph nodes (UnLN) and paired lymph nodes with metastases (LNM) from five breast cancer patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The proteome was analyzed for cortical lymphocyte compartments, subcapsular sinus (SCS) and medullary sinus (MS) CD169\n                      <jats:sup>+<\/jats:sup>\n                      macrophages, using the Digital Spatial Profiling (DSP) platform from NanoString.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our results identified a stable proteome of SCS CD169\n                      <jats:sup>+<\/jats:sup>\n                      macrophages in LNM, with the exception for downregulation of the anti-apoptotic protein Bcl-xL and FAP\u03b1, but a clear reduction in numbers of SCS CD169\n                      <jats:sup>+<\/jats:sup>\n                      macrophages in LNM. In contrast, the proteome of MS CD169\n                      <jats:sup>+<\/jats:sup>\n                      macrophages, B-cell compartments and interfollicular T-cells showed altered immune signatures in LNM, indicating that the decline in SCS CD169\n                      <jats:sup>+<\/jats:sup>\n                      macrophages coincide with a malfunction in the local, anti-tumor immune responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The findings from our study support the notion that metastasis to lymph nodes in breast cancer patients modifies local immune responses. These changes may contribute to explain unsuccessful therapeutic responses, and thereby worsened prognosis, for breast cancer patients with LNM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-025-06415-4","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T10:12:16Z","timestamp":1744279936000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Altered immune signatures in breast cancer lymph nodes with metastases revealed by spatial proteome analyses"],"prefix":"10.1186","volume":"23","author":[{"given":"Oscar","family":"Briem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bal\u00e1zs","family":"Tahin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asger Meldgaard","family":"Frank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Olsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Sandstr\u00f6m","family":"Gerdtsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"K\u00e4llberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8254-3137","authenticated-orcid":false,"given":"Karin","family":"Leandersson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,10]]},"reference":[{"issue":"17","key":"6415_CR1","first-page":"4287","volume":"13","author":"S \u0141ukasiewicz","year":"2021","unstructured":"\u0141ukasiewicz S, Czeczelewski M, Forma A, Baj J, Sitarz R, Stanis\u0142awek A, Breast, Cancer\u2014Epidemiology. Risk factors, classification, prognostic markers, and current treatment Strategies\u2014An. Updated Rev Cancers. 2021;13(17):4287.","journal-title":"Updated Rev Cancers"},{"issue":"1","key":"6415_CR2","doi-asserted-by":"publisher","first-page":"2259","DOI":"10.1038\/s41598-021-81538-4","volume":"11","author":"M Rossing","year":"2021","unstructured":"Rossing M, Pedersen CB, Tvedskov T, Vejborg I, Talman M-L, Olsen LR, et al. Clinical implications of intrinsic molecular subtypes of breast cancer for Sentinel node status. Sci Rep. 2021;11(1):2259.","journal-title":"Sci Rep"},{"key":"6415_CR3","doi-asserted-by":"crossref","unstructured":"Liu J, Li Y, Zhang W, Yang C, Yang C, Chen L et al. The prognostic role of lymph node ratio in breast cancer patients received neoadjuvant chemotherapy: A dose-response meta-analysis. Front Surg. 2022;9.","DOI":"10.3389\/fsurg.2022.971030"},{"key":"6415_CR4","doi-asserted-by":"crossref","unstructured":"Ping J, Liu W, Chen Z, Li C. Lymph node metastases in breast cancer: mechanisms and molecular imaging. Clin Imaging. 2023;103.","DOI":"10.1016\/j.clinimag.2023.109985"},{"key":"6415_CR5","doi-asserted-by":"crossref","unstructured":"Lei PJ, Pereira ER, Andersson P, Amoozgar Z, Van Wijnbergen JW, O\u2019Melia MJ et al. Cancer cell plasticity and MHC-II-mediated immune tolerance promote breast cancer metastasis to lymph nodes. J Exp Med. 2023;220(9).","DOI":"10.1084\/jem.20221847"},{"issue":"6382","key":"6415_CR6","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1126\/science.aal3662","volume":"359","author":"M Brown","year":"2018","unstructured":"Brown M, Assen FP, Leithner A, Abe J, Schachner H, Asfour G, et al. Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice. Science. 2018;359(6382):1408\u201311.","journal-title":"Science"},{"issue":"6382","key":"6415_CR7","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1126\/science.aal3622","volume":"359","author":"ER Pereira","year":"2018","unstructured":"Pereira ER, Kedrin D, Seano G, Gautier O, Meijer EFJ, Jones D, et al. Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice. Science. 2018;359(6382):1403\u20137.","journal-title":"Science"},{"issue":"11","key":"6415_CR8","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1016\/j.cell.2022.04.019","volume":"185","author":"NE Reticker-Flynn","year":"2022","unstructured":"Reticker-Flynn NE, Zhang W, Belk JA, Basto PA, Escalante NK, Pilarowski GOW, et al. Lymph node colonization induces tumor-immune tolerance to promote distant metastasis. Cell. 2022;185(11):1924\u2013e4223.","journal-title":"Cell"},{"issue":"8","key":"6415_CR9","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1016\/j.ccell.2022.06.009","volume":"40","author":"A van Krimpen","year":"2022","unstructured":"van Krimpen A, Gerretsen VIV, Mulder E, van Gulijk M, van den Bosch TPP, von der Thusen J, et al. Immune suppression in the tumor-draining lymph node corresponds with distant disease recurrence in patients with melanoma. Cancer Cell. 2022;40(8):798\u20139.","journal-title":"Cancer Cell"},{"issue":"1","key":"6415_CR10","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/s41392-023-01576-4","volume":"8","author":"H Ji","year":"2023","unstructured":"Ji H, Hu C, Yang X, Liu Y, Ji G, Ge S, et al. Lymph node metastasis in cancer progression: molecular mechanisms, clinical significance and therapeutic interventions. Signal Transduct Target Therapy. 2023;8(1):367.","journal-title":"Signal Transduct Target Therapy"},{"issue":"5","key":"6415_CR11","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/s41577-023-00965-8","volume":"24","author":"P Cruz de Casas","year":"2024","unstructured":"Cruz de Casas P, Kn\u00f6pper K, Dey Sarkar R, Kastenm\u00fcller W. Same yet different \u2014 how lymph node heterogeneity affects immune responses. Nat Rev Immunol. 2024;24(5):358\u201374.","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"6415_CR12","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1038\/s41467-019-14134-w","volume":"11","author":"F Pelon","year":"2020","unstructured":"Pelon F, Bourachot B, Kieffer Y, Magagna I, Mermet-Meillon F, Bonnet I, et al. Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nat Commun. 2020;11(1):404.","journal-title":"Nat Commun"},{"issue":"1","key":"6415_CR13","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1002\/cjp2.87","volume":"4","author":"A Grigoriadis","year":"2018","unstructured":"Grigoriadis A, Gazinska P, Pai T, Irhsad S, Wu Y, Millis R, et al. Histological scoring of immune and stromal features in breast and axillary lymph nodes is prognostic for distant metastasis in lymph node-positive breast cancers. J Pathol Clin Res. 2018;4(1):39\u201354.","journal-title":"J Pathol Clin Res"},{"key":"6415_CR14","doi-asserted-by":"crossref","unstructured":"Alberts E, Wall I, Calado DP, Grigoriadis A. Immune crosstalk between lymph nodes and breast carcinomas, with a focus on B cells. Front Mol Biosci. 2021;8.","DOI":"10.3389\/fmolb.2021.673051"},{"issue":"1","key":"6415_CR15","doi-asserted-by":"publisher","first-page":"1848067","DOI":"10.1080\/2162402X.2020.1848067","volume":"9","author":"F Bjork Gunnarsdottir","year":"2020","unstructured":"Bjork Gunnarsdottir F, Auoja N, Bendahl PO, Ryden L, Ferno M, Leandersson K. Co-localization of CD169(+) macrophages and cancer cells in lymph node metastases of breast cancer patients is linked to improved prognosis and PDL1 expression. Oncoimmunology. 2020;9(1):1848067.","journal-title":"Oncoimmunology"},{"issue":"1","key":"6415_CR16","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1177\/0194599819829741","volume":"161","author":"MC Topf","year":"2019","unstructured":"Topf MC, Harshyne L, Tuluc M, Mardekian S, Vimawala S, Cognetti DM, et al. Loss of CD169\u2009+\u2009Subcapsular macrophages during metastatic spread of head and neck squamous cell carcinoma. Otolaryngology\u2013Head Neck Surg. 2019;161(1):67\u201373.","journal-title":"Otolaryngology\u2013Head Neck Surg"},{"issue":"2","key":"6415_CR17","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1002\/path.4720","volume":"239","author":"Y Zhang","year":"2016","unstructured":"Zhang Y, Li JQ, Jiang ZZ, Li L, Wu Y, Zheng L. CD169 identifies an anti-tumour macrophage subpopulation in human hepatocellular carcinoma. J Pathol. 2016;239(2):231\u201341.","journal-title":"J Pathol"},{"issue":"6","key":"6415_CR18","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1111\/cas.12929","volume":"107","author":"K Ohnishi","year":"2016","unstructured":"Ohnishi K, Yamaguchi M, Erdenebaatar C, Saito F, Tashiro H, Katabuchi H, et al. Prognostic significance of CD169-positive lymph node sinus macrophages in patients with endometrial carcinoma. Cancer Sci. 2016;107(6):846\u201352.","journal-title":"Cancer Sci"},{"issue":"12","key":"6415_CR19","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1158\/2326-6066.CIR-14-0180","volume":"3","author":"Y Saito","year":"2015","unstructured":"Saito Y, Ohnishi K, Miyashita A, Nakahara S, Fujiwara Y, Horlad H, et al. Prognostic significance of CD169\u2009+\u2009Lymph node sinus macrophages in patients with malignant melanoma. Cancer Immunol Res. 2015;3(12):1356\u201363.","journal-title":"Cancer Immunol Res"},{"issue":"9","key":"6415_CR20","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1111\/cas.12212","volume":"104","author":"K Ohnishi","year":"2013","unstructured":"Ohnishi K, Komohara Y, Saito Y, Miyamoto Y, Watanabe M, Baba H, et al. CD169-positive macrophages in regional lymph nodes are associated with a favorable prognosis in patients with colorectal carcinoma. Cancer Sci. 2013;104(9):1237\u201344.","journal-title":"Cancer Sci"},{"key":"6415_CR21","doi-asserted-by":"crossref","unstructured":"Briem O, Kallberg E, Kimbung S, Veerla S, Stenstrom J, Hatschek T et al. CD169(+) macrophages in primary breast tumors associate with tertiary lymphoid structures, T(regs) and a worse prognosis for patients with advanced breast cancer. Cancers (Basel). 2023;15(4).","DOI":"10.3390\/cancers15041262"},{"issue":"11","key":"6415_CR22","doi-asserted-by":"publisher","first-page":"e0166680","DOI":"10.1371\/journal.pone.0166680","volume":"11","author":"T Shiota","year":"2016","unstructured":"Shiota T, Miyasato Y, Ohnishi K, Yamamoto-Ibusuki M, Yamamoto Y, Iwase H, et al. The clinical significance of CD169-Positive lymph node macrophage in patients with breast cancer. PLoS ONE. 2016;11(11):e0166680\u2013e.","journal-title":"PLoS ONE"},{"issue":"2","key":"6415_CR23","doi-asserted-by":"publisher","first-page":"108993","DOI":"10.1016\/j.celrep.2021.108993","volume":"35","author":"C Tacconi","year":"2021","unstructured":"Tacconi C, Commerford CD, Dieterich LC, Schwager S, He Y, Ikenberg K, et al. CD169\u2009+\u2009lymph node macrophages have protective functions in mouse breast cancer metastasis. Cell Rep. 2021;35(2):108993.","journal-title":"Cell Rep"},{"key":"6415_CR24","doi-asserted-by":"publisher","first-page":"1180209","DOI":"10.3389\/fimmu.2023.1180209","volume":"14","author":"FB Gunnarsdottir","year":"2023","unstructured":"Gunnarsdottir FB, Briem O, Lindgren AY, Kallberg E, Andersen C, Grenthe R, et al. Breast cancer associated CD169(+) macrophages possess broad immunosuppressive functions but enhance antibody secretion by activated B cells. Front Immunol. 2023;14:1180209.","journal-title":"Front Immunol"},{"key":"6415_CR25","doi-asserted-by":"crossref","unstructured":"Louie DAP, Liao S. Lymph node subcapsular sinus macrophages as the frontline of lymphatic immune defense. Front Immunol. 2019;10.","DOI":"10.3389\/fimmu.2019.00347"},{"issue":"1","key":"6415_CR26","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.immuni.2010.12.011","volume":"34","author":"K Asano","year":"2011","unstructured":"Asano K, Nabeyama A, Miyake Y, Qiu CH, Kurita A, Tomura M, et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity. 2011;34(1):85\u201395.","journal-title":"Immunity"},{"issue":"4","key":"6415_CR27","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1038\/icb.2015.29","volume":"93","author":"JR Groom","year":"2015","unstructured":"Groom JR. Moving to the suburbs: T-cell positioning within lymph nodes during activation and memory. Immunol Cell Biol. 2015;93(4):330\u20136.","journal-title":"Immunol Cell Biol"},{"issue":"2","key":"6415_CR28","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/ni1557","volume":"9","author":"HD Hickman","year":"2008","unstructured":"Hickman HD, Takeda K, Skon CN, Murray FR, Hensley SE, Loomis J, et al. Direct priming of antiviral CD8\u2009+\u2009T cells in the peripheral interfollicular region of lymph nodes. Nat Immunol. 2008;9(2):155\u201365.","journal-title":"Nat Immunol"},{"issue":"2","key":"6415_CR29","doi-asserted-by":"publisher","first-page":"26","DOI":"10.3892\/br.2020.1402","volume":"14","author":"Y Liu","year":"2021","unstructured":"Liu Y, Xia Y, Qiu CH. Functions of CD169 positive macrophages in human diseases (Review). Biomed Rep. 2021;14(2):26.","journal-title":"Biomed Rep"},{"issue":"5\u20136","key":"6415_CR30","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1159\/000337007","volume":"4","author":"EE Gray","year":"2012","unstructured":"Gray EE, Cyster JG. Lymph node macrophages. J Innate Immun. 2012;4(5\u20136):424\u201336.","journal-title":"J Innate Immun"},{"issue":"29","key":"6415_CR31","doi-asserted-by":"publisher","first-page":"E6826","DOI":"10.1073\/pnas.1712628115","volume":"115","author":"HY Huang","year":"2018","unstructured":"Huang HY, Rivas-Caicedo A, Renevey F, Cannelle H, Peranzoni E, Scarpellino L, et al. Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis. Proc Natl Acad Sci U S A. 2018;115(29):E6826\u201335.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"6415_CR32","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1038\/ni.1946","volume":"11","author":"JG Cyster","year":"2010","unstructured":"Cyster JG. B cell follicles and antigen encounters of the third kind. Nat Immunol. 2010;11(11):989\u201396.","journal-title":"Nat Immunol"},{"issue":"9","key":"6415_CR33","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1038\/s41423-023-01060-7","volume":"20","author":"E Playoust","year":"2023","unstructured":"Playoust E, Remark R, Vivier E, Milpied P. Germinal center-dependent and -independent immune responses of tumor-infiltrating B cells in human cancers. Cell Mol Immunol. 2023;20(9):1040\u201350.","journal-title":"Cell Mol Immunol"},{"issue":"7","key":"6415_CR34","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1016\/j.cell.2022.02.012","volume":"185","author":"RD Mazor","year":"2022","unstructured":"Mazor RD, Nathan N, Gilboa A, Stoler-Barak L, Moss L, Solomonov I, et al. Tumor-reactive antibodies evolve from non-binding and autoreactive precursors. Cell. 2022;185(7):1208\u2013e2221.","journal-title":"Cell"},{"issue":"6Supplement","key":"6415_CR35","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1158\/1538-7445.AM2024-106","volume":"84","author":"Y Maeshima","year":"2024","unstructured":"Maeshima Y, Kataoka TR, Vandenbon A, Hirata M, Takeuchi Y, Suzuki Y, et al. Selective elimination of CD169\u2009+\u2009macrophages in lymph nodes invaded by breast cancers. Cancer Res. 2024;84(6Supplement):106.","journal-title":"Cancer Res"},{"key":"6415_CR36","doi-asserted-by":"publisher","first-page":"105271","DOI":"10.1016\/j.ebiom.2024.105271","volume":"107","author":"Y Maeshima","year":"2024","unstructured":"Maeshima Y, Kataoka TR, Vandenbon A, Hirata M, Takeuchi Y, Suzuki Y, et al. Intra-patient Spatial comparison of non-metastatic and metastatic lymph nodes reveals the reduction of CD169(+) macrophages by metastatic breast cancers. EBioMedicine. 2024;107:105271.","journal-title":"EBioMedicine"},{"issue":"3","key":"6415_CR37","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1111\/cas.13137","volume":"108","author":"Y Komohara","year":"2017","unstructured":"Komohara Y, Ohnishi K, Takeya M. Possible functions of CD169-positive sinus macrophages in lymph nodes in anti-tumor immune responses. Cancer Sci. 2017;108(3):290\u20135.","journal-title":"Cancer Sci"},{"issue":"2","key":"6415_CR38","doi-asserted-by":"publisher","first-page":"143","DOI":"10.4048\/jbc.2015.18.2.143","volume":"18","author":"MD Mattes","year":"2015","unstructured":"Mattes MD, Bhatia JK, Metzger D, Ashamalla H, Katsoulakis E. Breast cancer subtype as a predictor of lymph node metastasis according to the SEER registry. J Breast Cancer. 2015;18(2):143\u20138.","journal-title":"J Breast Cancer"},{"key":"6415_CR39","doi-asserted-by":"crossref","unstructured":"Tong ZJ, Shi NY, Zhang ZJ, Yuan XD, Hong XM. Expression and prognostic value of HER-2\/neu in primary breast cancer with Sentinel lymph node metastasis. Biosci Rep. 2017;37(4).","DOI":"10.1042\/BSR20170121"},{"key":"6415_CR40","doi-asserted-by":"publisher","first-page":"13050","DOI":"10.1038\/ncomms13050","volume":"7","author":"R Allaoui","year":"2016","unstructured":"Allaoui R, Bergenfelz C, Mohlin S, Hagerling C, Salari K, Werb Z, et al. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Nat Commun. 2016;7:13050.","journal-title":"Nat Commun"},{"issue":"1","key":"6415_CR41","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s13058-015-0621-0","volume":"17","author":"S Sousa","year":"2015","unstructured":"Sousa S, Brion R, Lintunen M, Kronqvist P, Sandholm J, Monkkonen J, et al. Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Res. 2015;17(1):101.","journal-title":"Breast Cancer Res"},{"issue":"14","key":"6415_CR42","doi-asserted-by":"publisher","first-page":"1825","DOI":"10.1038\/onc.2011.370","volume":"31","author":"F Stossi","year":"2012","unstructured":"Stossi F, Madak-Erdogan Z, Katzenellenbogen BS. Macrophage-elicited loss of Estrogen receptor-alpha in breast cancer cells via involvement of MAPK and c-Jun at the ESR1 genomic locus. Oncogene. 2012;31(14):1825\u201334.","journal-title":"Oncogene"},{"issue":"1","key":"6415_CR43","doi-asserted-by":"publisher","first-page":"111932","DOI":"10.1016\/j.yexcr.2020.111932","volume":"390","author":"FB Gunnarsdottir","year":"2020","unstructured":"Gunnarsdottir FB, Hagerling C, Bergenfelz C, Mehmeti M, Kallberg E, Allaoui R, et al. Inflammatory macrophage derived TNFalpha downregulates Estrogen receptor alpha via FOXO3a inactivation in human breast cancer cells. Exp Cell Res. 2020;390(1):111932.","journal-title":"Exp Cell Res"},{"key":"6415_CR44","doi-asserted-by":"crossref","unstructured":"Zhang X, Yang F, Huang Z, Liu X, Xia G, Huang J et al. Macrophages promote subtype conversion and endocrine resistance in breast cancer. Cancers (Basel). 2024;16(3).","DOI":"10.3390\/cancers16030678"},{"issue":"21","key":"6415_CR45","doi-asserted-by":"publisher","first-page":"17800","DOI":"10.1074\/jbc.M008270200","volume":"276","author":"L Sevilla","year":"2001","unstructured":"Sevilla L, Zaldumbide A, Carlotti F, Dayem MA, Pognonec P, Boulukos KE. Bcl-XL expression correlates with primary macrophage differentiation, activation of functional competence, and survival and results from synergistic transcriptional activation by Ets2 and PU.1. J Biol Chem. 2001;276(21):17800\u20137.","journal-title":"J Biol Chem"},{"issue":"33","key":"6415_CR46","doi-asserted-by":"publisher","first-page":"12139","DOI":"10.1073\/pnas.1412910111","volume":"111","author":"AE Denton","year":"2014","unstructured":"Denton AE, Roberts EW, Linterman MA, Fearon DT. Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8\u2009+\u2009T cells. Proc Natl Acad Sci U S A. 2014;111(33):12139\u201344.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"6415_CR47","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1002\/eji.202249879","volume":"52","author":"X Chen","year":"2022","unstructured":"Chen X, Zheng Y, Liu S, Yu W, Liu Z. CD169(+) subcapsular sinus macrophage-derived microvesicles are associated with light zone follicular dendritic cells. Eur J Immunol. 2022;52(10):1581\u201394.","journal-title":"Eur J Immunol"},{"key":"6415_CR48","first-page":"87","volume":"2","author":"NE Harwood","year":"2010","unstructured":"Harwood NE, Batista FD. Antigen presentation to B cells. F1000. Biol Rep. 2010;2:87.","journal-title":"Biol Rep"},{"issue":"3","key":"6415_CR49","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/mi.2012.100","volume":"6","author":"LA Albacker","year":"2013","unstructured":"Albacker LA, Yu S, Bedoret D, Lee WL, Umetsu SE, Monahan S, et al. TIM-4, expressed by medullary macrophages, regulates respiratory tolerance by mediating phagocytosis of antigen-specific T cells. Mucosal Immunol. 2013;6(3):580\u201390.","journal-title":"Mucosal Immunol"},{"key":"6415_CR50","doi-asserted-by":"crossref","unstructured":"Solinas C, Gu-Trantien C, Willard-Gallo K. The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy. ESMO Open. 2020;5(1).","DOI":"10.1136\/esmoopen-2019-000544"},{"issue":"1","key":"6415_CR51","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1182\/blood-2017-06-741033","volume":"131","author":"B Rowshanravan","year":"2018","unstructured":"Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58\u201367.","journal-title":"Blood"},{"issue":"2","key":"6415_CR52","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1152\/physrev.00037.2016","volume":"98","author":"RW Caldwell","year":"2018","unstructured":"Caldwell RW, Rodriguez PC, Toque HA, Narayanan SP, Caldwell RB. Arginase: A multifaceted enzyme important in health and disease. Physiol Rev. 2018;98(2):641\u201365.","journal-title":"Physiol Rev"},{"key":"6415_CR53","doi-asserted-by":"crossref","unstructured":"Zhou Z, He H, Wang K, Shi X, Wang Y, Su Y et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science. 2020;368(6494).","DOI":"10.1126\/science.aaz7548"},{"issue":"1","key":"6415_CR54","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1038\/s41467-020-15543-y","volume":"11","author":"E Cano-Gamez","year":"2020","unstructured":"Cano-Gamez E, Soskic B, Roumeliotis TI, So E, Smyth DJ, Baldrighi M, et al. Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4\u2009+\u2009T cells to cytokines. Nat Commun. 2020;11(1):1801.","journal-title":"Nat Commun"},{"key":"6415_CR55","doi-asserted-by":"publisher","first-page":"931","DOI":"10.3389\/fimmu.2020.00931","volume":"11","author":"KR van Daalen","year":"2020","unstructured":"van Daalen KR, Reijneveld JF, Bovenschen N. Modulation of inflammation by extracellular granzyme A. Front Immunol. 2020;11:931.","journal-title":"Front Immunol"},{"issue":"5","key":"6415_CR56","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.immuni.2008.08.014","volume":"29","author":"SS Metkar","year":"2008","unstructured":"Metkar SS, Menaa C, Pardo J, Wang B, Wallich R, Freudenberg M, et al. Human and mouse granzyme A induce a Proinflammatory cytokine response. Immunity. 2008;29(5):720\u201333.","journal-title":"Immunity"},{"issue":"9","key":"6415_CR57","doi-asserted-by":"publisher","first-page":"2294","DOI":"10.1271\/bbb.80140","volume":"72","author":"H Hirayasu","year":"2008","unstructured":"Hirayasu H, Yoshikawa Y, Tsuzuki S, Fushiki T. A lymphocyte Serine protease granzyme A causes detachment of a small-intestinal epithelial cell line (IEC-6). Biosci Biotechnol Biochem. 2008;72(9):2294\u2013302.","journal-title":"Biosci Biotechnol Biochem"},{"issue":"6","key":"6415_CR58","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1038\/ni.1877","volume":"11","author":"KL Good-Jacobson","year":"2010","unstructured":"Good-Jacobson KL, Szumilas CG, Chen L, Sharpe AH, Tomayko MM, Shlomchik MJ. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol. 2010;11(6):535\u201342.","journal-title":"Nat Immunol"},{"issue":"11","key":"6415_CR59","doi-asserted-by":"publisher","first-page":"2280","DOI":"10.1182\/blood-2009-03-208215","volume":"114","author":"S Middendorp","year":"2009","unstructured":"Middendorp S, Xiao Y, Song J-Y, Peperzak V, Krijger PHL, Jacobs H, et al. Mice deficient for CD137 ligand are predisposed to develop germinal center\u2013derived B-cell lymphoma. Blood. 2009;114(11):2280\u20139.","journal-title":"Blood"},{"issue":"4","key":"6415_CR60","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1046\/j.1365-3083.2003.01217.x","volume":"57","author":"M Lindstedt","year":"2003","unstructured":"Lindstedt M, Johansson-Lindbom B, Borrebaeck CA. Expression of CD137 (4-1BB) on human follicular dendritic cells. Scand J Immunol. 2003;57(4):305\u201310.","journal-title":"Scand J Immunol"},{"issue":"4","key":"6415_CR61","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1093\/intimm\/dxg037","volume":"15","author":"C Chalouni","year":"2003","unstructured":"Chalouni C, Banchereau J, Vogt AB, Pascual V, Davoust J. Human germinal center B cells differ from Naive and memory B cells by their aggregated MHC class II-rich compartments lacking HLA\u2010DO. Int Immunol. 2003;15(4):457\u201366.","journal-title":"Int Immunol"},{"issue":"10","key":"6415_CR62","doi-asserted-by":"publisher","first-page":"e20210790","DOI":"10.1084\/jem.20210790","volume":"218","author":"BA Heesters","year":"2021","unstructured":"Heesters BA, van Megesen K, Tomris I, de Vries RP, Magri G, Spits H. Characterization of human FDCs reveals regulation of T cells and antigen presentation to B cells. J Exp Med. 2021;218(10):e20210790.","journal-title":"J Exp Med"},{"issue":"3","key":"6415_CR63","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1084\/jem.183.3.971","volume":"183","author":"H Martinez-Valdez","year":"1996","unstructured":"Martinez-Valdez H, Guret C, de Bouteiller O, Fugier I, Banchereau J, Liu YJ. Human germinal center B cells express the apoptosis-inducing genes Fas, c-myc, P53, and Bax but not the survival gene bcl-2. J Exp Med. 1996;183(3):971\u20137.","journal-title":"J Exp Med"},{"issue":"1","key":"6415_CR64","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1006\/cimm.1996.0260","volume":"173","author":"X Zhang","year":"1996","unstructured":"Zhang X, Li L, Choe J, Krajewski S, Reed JC, Thompson C, et al. Up-Regulation of Bcl-xLExpression protects CD40-Activated human B cells from Fas-Mediated apoptosis. Cell Immunol. 1996;173(1):149\u201354.","journal-title":"Cell Immunol"},{"issue":"8","key":"6415_CR65","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1002\/eji.1830210819","volume":"21","author":"Y-J Liu","year":"1991","unstructured":"Liu Y-J, Mason DY, Johnson GD, Abbot S, Gregory CD, Hardie DL, et al. Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis. Eur J Immunol. 1991;21(8):1905\u201310.","journal-title":"Eur J Immunol"},{"issue":"1","key":"6415_CR66","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1002\/eji.201444911","volume":"45","author":"H Li","year":"2015","unstructured":"Li H, Pauza CD. CD25(+) Bcl6(low) T follicular helper cells provide help to maturing B cells in germinal centers of human tonsil. Eur J Immunol. 2015;45(1):298\u2013308.","journal-title":"Eur J Immunol"},{"issue":"7","key":"6415_CR67","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1016\/j.celrep.2019.10.012","volume":"29","author":"E Shen","year":"2019","unstructured":"Shen E, Rabe H, Luo L, Wang L, Wang Q, Yin J, et al. Control of germinal center localization and lineage stability of follicular regulatory T cells by the Blimp1 transcription factor. Cell Rep. 2019;29(7):1848\u2013e616.","journal-title":"Cell Rep"},{"issue":"2","key":"6415_CR68","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1084\/jem.20141432","volume":"212","author":"JP Weber","year":"2015","unstructured":"Weber JP, Fuhrmann F, Feist RK, Lahmann A, Al Baz MS, Gentz LJ, et al. ICOS maintains the T follicular helper cell phenotype by down-regulating Kruppel-like factor 2. J Exp Med. 2015;212(2):217\u201333.","journal-title":"J Exp Med"},{"key":"6415_CR69","doi-asserted-by":"crossref","unstructured":"Arulraj T, Binder SC, Robert PA, Meyer-Hermann M. Germinal Centre Shutdown Front Immunol. 2021;12.","DOI":"10.3389\/fimmu.2021.705240"},{"issue":"8","key":"6415_CR70","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/nm.2426","volume":"17","author":"Y Chung","year":"2011","unstructured":"Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011;17(8):983\u20138.","journal-title":"Nat Med"},{"issue":"8","key":"6415_CR71","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1038\/nm.2425","volume":"17","author":"MA Linterman","year":"2011","unstructured":"Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, et al. Foxp3\u2009+\u2009follicular regulatory T cells control the germinal center response. Nat Med. 2011;17(8):975\u201382.","journal-title":"Nat Med"},{"issue":"6552","key":"6415_CR72","doi-asserted-by":"publisher","first-page":"eabe5146","DOI":"10.1126\/science.abe5146","volume":"373","author":"JT Jacobsen","year":"2021","unstructured":"Jacobsen JT, Hu W, Castro R, Solem TB, Galante S, Lin A. Expression of Foxp3 by T follicular helper cells in end-stage germinal centers. Science. 2021;373(6552):eabe5146.","journal-title":"Science"},{"issue":"12","key":"6415_CR73","doi-asserted-by":"publisher","first-page":"1568","DOI":"10.1158\/2326-6066.CIR-20-0034","volume":"8","author":"RCA Sainson","year":"2020","unstructured":"Sainson RCA, Thotakura AK, Kosmac M, Borhis G, Parveen N, Kimber R, et al. An antibody targeting ICOS increases intratumoral cytotoxic to regulatory T-cell ratio and induces tumor regression. Cancer Immunol Res. 2020;8(12):1568\u201382.","journal-title":"Cancer Immunol Res"},{"key":"6415_CR74","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.3389\/fimmu.2020.02104","volume":"11","author":"DY Li","year":"2020","unstructured":"Li DY, Xiong XZ. ICOS(+) Tregs: A functional subset of Tregs in immune diseases. Front Immunol. 2020;11:2104.","journal-title":"Front Immunol"},{"issue":"6","key":"6415_CR75","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/j.cell.2023.02.021","volume":"186","author":"MK Rahim","year":"2023","unstructured":"Rahim MK, Okholm TLH, Jones KB, McCarthy EE, Liu CC, Yee JL, et al. Dynamic CD8(+) T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. 2023;186(6):1127\u2013e4318.","journal-title":"Cell"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-06415-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-025-06415-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-06415-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T12:16:07Z","timestamp":1757160967000},"score":1,"resource":{"primary":{"URL":"https:\/\/translational-medicine.biomedcentral.com\/articles\/10.1186\/s12967-025-06415-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,10]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["6415"],"URL":"https:\/\/doi.org\/10.1186\/s12967-025-06415-4","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,10]]},"assertion":[{"value":"15 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2025","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This article has been updated to amend the license information.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained by the Swedish Ethical Review Authority (Dnr 2021\u201304869).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"All authors read, revised and approved the final manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Authors declare no competing interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"422"}}