{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:05:00Z","timestamp":1790679900233,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T00:00:00Z","timestamp":1651708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation","award":["WE4892\/3-1"],"award-info":[{"award-number":["WE4892\/3-1"]}]},{"name":"German Research Foundation","award":["WE4892\/4-1"],"award-info":[{"award-number":["WE4892\/4-1"]}]},{"name":"German Research Foundation","award":["WE4892\/8-1"],"award-info":[{"award-number":["WE4892\/8-1"]}]},{"name":"German Research Foundation","award":["WE4892\/9-1"],"award-info":[{"award-number":["WE4892\/9-1"]}]},{"name":"Boehringer Ingelheim","award":["WE4892\/3-1"],"award-info":[{"award-number":["WE4892\/3-1"]}]},{"name":"Boehringer Ingelheim","award":["WE4892\/4-1"],"award-info":[{"award-number":["WE4892\/4-1"]}]},{"name":"Boehringer Ingelheim","award":["WE4892\/8-1"],"award-info":[{"award-number":["WE4892\/8-1"]}]},{"name":"Boehringer Ingelheim","award":["WE4892\/9-1"],"award-info":[{"award-number":["WE4892\/9-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Immunotherapy has become increasingly important in the treatment of colorectal cancer (CRC). Currently, CD73, also known as ecto-5\u2032-nucleotidase (NT5E), has gained considerable interest as a potential therapeutic target. CD73 is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects. However, the role of CD73 expression on various cell types within the CRC tumor microenvironment remains unresolved. The expression of CD73 on various cell types has been described recently, but the role of CD73 on B-cells in CRC remains unclear. Therefore, we analyzed CD73 on B-cells, especially on tumor-infiltrating B-cells, in paired tumor and adjacent normal tissue samples from 62 eligible CRC patients. The highest expression of CD73 on tumor-infiltrating B-cells was identified on class-switched memory B-cells, followed by naive B-cells, whereas no CD73 expression was observed on plasmablasts. Clinicopathological correlation analysis revealed that higher CD73+ B-cells infiltration in the CRC tumors was associated with better overall survival. Moreover, metastasized patients showed a significantly decreased number of tumor-infiltrating CD73+ B-cells. Finally, neoadjuvant therapy correlated with reduced CD73+ B-cell numbers and CD73 expression on B-cells in the CRC tumors. As promising new immune therapies are being developed, the role of CD73+ B-cells and their subsets in the development of colorectal cancer should be further explored to find new therapeutic options.<\/jats:p>","DOI":"10.3390\/ijms23095163","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T13:10:26Z","timestamp":1651756226000},"page":"5163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Tumor Infiltration with CD20+CD73+ B Cells Correlates with Better Outcome in Colorectal Cancer"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7452-1189","authenticated-orcid":false,"given":"Frederik J.","family":"Hansen","sequence":"first","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2527-0635","authenticated-orcid":false,"given":"Zhiyuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"David","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Mittelst\u00e4dt","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Jacobsen","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata J.","family":"Podolska","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenia","family":"Ubieta","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Brunner","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Kouhestani","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela","family":"Swierzy","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotta","family":"Ro\u00dfdeutsch","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Kl\u00f6sch","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Kutschick","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2676-9486","authenticated-orcid":false,"given":"Susanne","family":"Merkel","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Denz","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Geppert","sequence":"additional","affiliation":[{"name":"Department of Pathology, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Gr\u00fctzmann","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"B\u00e9nard","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1175-4505","authenticated-orcid":false,"given":"Georg F.","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Friedrich-Alexander-University, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1016\/S0140-6736(19)32319-0","article-title":"Colorectal cancer","volume":"394","author":"Dekker","year":"2019","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/s41575-019-0126-x","article-title":"Immunotherapy in colorectal cancer: Rationale, challenges and potential","volume":"16","author":"Ganesh","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/978-981-15-3266-5_9","article-title":"Functions of Immune Checkpoint Molecules Beyond Immune Evasion","volume":"1248","author":"Zhang","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.bbamcr.2008.01.024","article-title":"Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade","volume":"1783","author":"Yegutkin","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/414916a","article-title":"Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage","volume":"414","author":"Ohta","year":"2001","journal-title":"Nature"},{"key":"ref_7","first-page":"2602","article-title":"The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine","volume":"57","author":"Blay","year":"1997","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"BSR20190101","DOI":"10.1042\/BSR20190101","article-title":"NT5E is associated with unfavorable prognosis and regulates cell proliferation and motility in gastric cancer","volume":"39","author":"Hu","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13045-019-0724-7","article-title":"CD73 promotes hepatocellular carcinoma progression and metastasis via activating PI3K\/AKT signaling by inducing Rap1-mediated membrane localization of P110beta and predicts poor prognosis","volume":"12","author":"Ma","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00109-018-01742-0","article-title":"The distinct role of CD73 in the progression of pancreatic cancer","volume":"97","author":"Zhou","year":"2019","journal-title":"J. Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/jso.23056","article-title":"High expression of CD73 as a poor prognostic biomarker in human colorectal cancer","volume":"106","author":"Wu","year":"2012","journal-title":"J. Surg. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5459","DOI":"10.1007\/s13277-015-3212-x","article-title":"The expression and clinical significance of CD73 molecule in human rectal adenocarcinoma","volume":"36","author":"Zhang","year":"2015","journal-title":"Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1002\/ijc.30138","article-title":"Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer","volume":"139","author":"Berntsson","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1182\/blood-2013-02-482406","article-title":"Adenosine production by human B cells and B cell-mediated suppression of activated T cells","volume":"122","author":"Saze","year":"2013","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/j.1399-0039.1990.tb01750.x","article-title":"Production and characterization of monoclonal antibodies to the glycosyl phosphatidylinositol-anchored lymphocyte differentiation antigen ecto-5\u2032-nucleotidase (CD73)","volume":"35","author":"Thomson","year":"1990","journal-title":"Tissue Antigens"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1158\/0008-5472.CAN-09-3109","article-title":"CD73 on Tumor Cells Impairs Antitumor T-Cell Responses: A Novel Mechanism of Tumor-Induced Immune Suppression","volume":"70","author":"Jin","year":"2010","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1158\/0008-5472.CAN-10-4246","article-title":"CD73-Deficient Mice Have Increased Antitumor Immunity and Are Resistant to Experimental Metastasis","volume":"71","author":"Stagg","year":"2011","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1158\/0008-5472.CAN-12-0420","article-title":"CD73-Deficient Mice Are Resistant to Carcinogenesis","volume":"72","author":"Stagg","year":"2012","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1002\/eji.201041292","article-title":"Altered purinergic signaling in CD73-deficient mice inhibits tumor progression","volume":"41","author":"Yegutkin","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/s41590-019-0427-9","article-title":"B cell signaling in context","volume":"20","author":"Kwak","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/nrc.2017.121","article-title":"Targeting B cell receptor signalling in cancer: Preclinical and clinical advances","volume":"18","author":"Burger","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4006","DOI":"10.4049\/jimmunol.0903009","article-title":"B Cells Are Required for Optimal CD4+ and CD8+ T Cell Tumor Immunity: Therapeutic B Cell Depletion Enhances B16 Melanoma Growth in Mice","volume":"184","author":"DiLillo","year":"2010","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.18632\/oncotarget.1701","article-title":"Characterization of tumor-associated B-cell subsets in patients with colorectal cancer","volume":"5","author":"Schlosser","year":"2014","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19997","DOI":"10.1038\/s41598-019-56441-8","article-title":"The Prognostic Importance of CD20(+) B lymphocytes in Colorectal Cancer and the Relation to Other Immune Cell subsets","volume":"9","author":"Edin","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e25443","DOI":"10.4161\/onci.25443","article-title":"B cell-regulated immune responses in tumor models and cancer patients","volume":"2","author":"Fremd","year":"2013","journal-title":"OncoImmunology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5904","DOI":"10.4049\/jimmunol.1400336","article-title":"A Novel Mechanism of B Cell\u2013Mediated Immune Suppression through CD73 Expression and Adenosine Production","volume":"193","author":"Kaku","year":"2014","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.4049\/jimmunol.1200744","article-title":"Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanoma","volume":"189","author":"Forte","year":"2012","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/imr.12528","article-title":"The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets","volume":"276","author":"Allard","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Conter, L.J., Song, E., Shlomchik, M.J., and Tomayko, M.M. (2014). CD73 expression is dynamically regulated in the germinal center and bone marrow plasma cells are diminished in its absence. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092009"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1084\/jem.20040915","article-title":"Crucial Role for Ecto-5\u2032-Nucleotidase (CD73) in Vascular Leakage during Hypoxia","volume":"200","author":"Thompson","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1172\/JCI0215337","article-title":"Ecto-5\u2032-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia","volume":"110","author":"Synnestvedt","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1172\/JCI79380","article-title":"Loss of CD73-mediated actin polymerization promotes endometrial tumor progression","volume":"126","author":"Bowser","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11091","DOI":"10.1073\/pnas.1222251110","article-title":"CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer","volume":"110","author":"Loi","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tsukui, H., Horie, H., Koinuma, K., Ohzawa, H., Sakuma, Y., Hosoya, Y., Yamaguchi, H., Yoshimura, K., Lefor, A.K., and Sata, N. (2020). CD73 blockade enhances the local and abscopal effects of radiotherapy in a murine rectal cancer model. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-06893-3"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5163\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:06:32Z","timestamp":1760137592000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5163"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,5]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23095163"],"URL":"https:\/\/doi.org\/10.3390\/ijms23095163","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,5]]}}}