{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:01:57Z","timestamp":1789970517912,"version":"4.0.1"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"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:p>\n                    B cells can suppress anti-tumor T cell responses, representing a potential mechanism of resistance to immunotherapy. Multiple Breg subsets have been described in humans and mice. Bregs inhibit anti-tumor immunity through cytokine secretion, immune checkpoint expression, and potentially adenosine generation, which collectively suppress effector T cells, and strengthen immunosuppressive signaling. Hypoxia is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to immune dysregulation within the tumor microenvironment (TME); however, the effects of hypoxia on B cell subsets remain poorly defined. In this study, we investigated how hypoxic stress shapes regulatory B cell phenotype using murine PDAC models. We show that nearly half of intratumoral B cells are hypoxic, which also increased across systemic B cell compartments with tumor burden. Hypoxic B cells were enriched for CD39 and CD73 ectonucleotidases and suppressed T cell activation via adenosine receptor\u2013dependent mechanisms. Hypoxia preferentially induced CD39\n                    <jats:sup>+<\/jats:sup>\n                    CD73\n                    <jats:sup>+<\/jats:sup>\n                    expression in peritoneal-derived B cells, indicating tissue-specific regulation, while splenic B cells showed limited responsiveness ex vivo. Conversely, hypoxia reduced IL-35 production by splenic Bregs through decreased Ebi3 expression and reduced activation marker levels. Within tumors, hypoxia correlated with CD11b\n                    <jats:sup>+<\/jats:sup>\n                    and CD39\n                    <jats:sup>+<\/jats:sup>\n                    CD73\n                    <jats:sup>+<\/jats:sup>\n                    B cells but not IL-35\u2013producing subsets. Mechanistically, Ebi3 loss enhanced CD39 expression under hypoxia, whereas recombinant IL-35 suppressed CD39\n                    <jats:sup>+<\/jats:sup>\n                    CD73\n                    <jats:sup>+<\/jats:sup>\n                    induction, suggesting reciprocal regulation between IL-35 and adenosine pathways. These findings reveal hypoxia-driven plasticity in immunosuppressive B cell programs in PDAC, characterized by suppression of IL-35\u2013producing Bregs and promotion of adenosine-generating CD39\n                    <jats:sup>+<\/jats:sup>\n                    CD73\n                    <jats:sup>+<\/jats:sup>\n                    B cells, highlighting potential therapeutic targets to modulate tumor-associated immunosuppression.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1814123","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:36:01Z","timestamp":1789968961000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamic regulation of hypoxia-associated regulatory CD39+CD73+ and IL35+ B cells in pancreatic cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Hannah R.","family":"Hall","sequence":"first","affiliation":[{"name":"Department of Pathology and 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