{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:07:32Z","timestamp":1785434852535,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,1]]},"group-title":"Immunology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01CA278852"],"award-info":[{"award-number":["R01CA278852"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["I01 CX001364"],"award-info":[{"award-number":["I01 CX001364"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Interferon regulatory factor 8 (IRF8) is a master transcription factor of myeloid differentiation, but whether IRF8 intrinsically controls B cell function in tumors remains unknown. Using paired single-cell transcriptomic and chromatin accessibility profiling of tumors from wild-type and Irf8-deficient mice, we identify a B cell-intrinsic IRF8 axis regulating antigen presentation and sustaining anti-tumor CD8\u207a T cell immunity. IRF8 establishes conserved chromatin accessibility programs across myeloid cells and plasmablasts centered on antigen processing and MHC class I presentation, but engages distinct motifs by lineage: myeloid cells preferentially utilize ISRE and ETS-composite elements, whereas plasmablasts are selectively enriched for EICE elements, reflecting B lineage-specific IRF8-IRF4 cooperation. Loss of IRF8 disrupts these programs, skews B cells toward plasmablast differentiation and reduces antigen presentation machinery. B cell depletion accelerated tumor growth, while CD40 agonism activated B cells, expanded T cells, and enhanced anti-tumor immunity. B cell-specific IRF8 deletion alone accelerated tumor growth, establishing a cell-intrinsic requirement independent of myeloid IRF8 function. The IRF8-regulated B cell signature was enriched in PD-1 blockade cancer patient responders, and plasmablast abundance correlated with response in pembrolizumab-treated cancer patients. These findings establish IRF8 as a lineage-adapted regulator of antigen presentation and define the IRF8-B cell axis as a determinant of anti-tumor immunity.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:p>IRF8 establishes a conserved chromatin accessibility across tumor-infiltrating myeloid and B cells<\/jats:p>\n                  <jats:p>Myeloid cells engage ISRE motifs, whereas plasmablasts rely on EICE motifs as IRF8 lineage-specific cis-regulation<\/jats:p>\n                  <jats:p>IRF8 regulates an antigen presentation in B cells to sustain anti-tumor T cell immunity<\/jats:p>\n                  <jats:p>B cell-intrinsic IRF8 transcription signature predicts patient response to PD-1 blockade immunotherapy<\/jats:p>\n                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