{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T01:51:35Z","timestamp":1793238695842,"version":"4.5.0"},"reference-count":258,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2020-112994RB-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2020-112994RB-I00\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010198","name":"Ministerio de Econom\u00eda, Industria y Competitividad, Gobierno de Espa\u00f1a","doi-asserted-by":"publisher","award":["SAF2017-82309-R\/MINECO\/AEI\/FEDER, EU"],"award-info":[{"award-number":["SAF2017-82309-R\/MINECO\/AEI\/FEDER, EU"]}],"id":[{"id":"10.13039\/501100010198","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003425","name":"Departamento de Educaci\u00f3n, Gobierno de Navarra","doi-asserted-by":"publisher","award":["Gobierno de Navarra 34E\/2020"],"award-info":[{"award-number":["Gobierno de Navarra 34E\/2020"]}],"id":[{"id":"10.13039\/501100003425","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"publisher","award":["RYC-2014-16399\/MEC"],"award-info":[{"award-number":["RYC-2014-16399\/MEC"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Besides a recognized role of PD-1\/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1\/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (TFH) and regulatory T (TFR) or B (Breg) cells are involved in positive selection of GC B cells and may result critical in the lymphoma microenvironment. Here, we discuss a role of PD-1\/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1\/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic\/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of TFR cells and limiting IL-21-mediated anti-tumour functions of TFH cells and maximize the use of PD-1\/PD-L1 signaling to escape from CD8+ cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1\/PD-L1-based combinational immunotherapies in DLBCL.<\/jats:p>","DOI":"10.3390\/cancers13184683","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T07:52:14Z","timestamp":1632124334000},"page":"4683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The PD-1\/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas"],"prefix":"10.3390","volume":"13","author":[{"given":"Marcos","family":"Garcia-Lacarte","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"},{"name":"Hemato-Oncology Program, Cima University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara C.","family":"Grijalba","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Melchor","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"},{"name":"Hemato-Oncology Program, Cima University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adri\u00e1n","family":"Arnaiz-Lech\u00e9","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Roa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain"},{"name":"Hemato-Oncology Program, Cima University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"},{"name":"Network Center for Biomedical Research in Cancer\u2014Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), Institute of Health Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1158\/2159-8290.CD-18-0367","article-title":"Fundamental Mechanisms of Immune Checkpoint Blockade Therapy","volume":"8","author":"Wei","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0065-2776(06)90008-X","article-title":"Checkpoint blockade in cancer immunotherapy","volume":"90","author":"Korman","year":"2006","journal-title":"Adv. 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