{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T04:34:49Z","timestamp":1777178089163,"version":"3.51.4"},"reference-count":24,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    PD-1\/PD-L1 immune checkpoint inhibitors (ICIs) demonstrate promising therapeutic potential in diffuse large B-cell lymphoma (DLBCL). However, a subset of DLBCL patients exhibits primary or acquired resistance to PD-1 blockade. This study investigated the mechanistic role of \u03b22-microglobulin (\n                    <jats:italic>B2M<\/jats:italic>\n                    ) mutations in modulating PD-L1 expression and their contribution to ICI resistance in DLBCL. The association between\n                    <jats:italic>B2M<\/jats:italic>\n                    mutations and PD-L1 expression in DLBCL patient samples was analyzed via immunohistochemistry. A\n                    <jats:italic>B2M<\/jats:italic>\n                    -knockout DLBCL cell line model was established, followed by evaluation of PD-L1 and MHC-I expression changes through qRT-PCR, western blot, and flow cytometry.\n                    <jats:italic>T<\/jats:italic>\n                    cell activation (CD69\/CD25 markers) and cytotoxic activity (lactate dehydrogenase release) were assessed in PBMC co-culture experiments. Mechanistic studies employing MHC-I inhibitors and IFN-\n                    <jats:italic>\u03b3<\/jats:italic>\n                    stimulation were conducted to dissect the regulatory relationship between MHC-I and PD-L1. Co-culture systems with PD-1 blockade was performed to validate the impact of\n                    <jats:italic>B2M<\/jats:italic>\n                    on PD-1 inhibitor resistance. The results demonstrated that\n                    <jats:italic>B2M<\/jats:italic>\n                    knockout significantly downregulated both PD-L1 mRNA and protein levels, concomitant with impaired MHC-I complex assembly and reduced TAP1\/2 expression.\n                    <jats:italic>B2M<\/jats:italic>\n                    -deficient cells failed to\u00a0activate CD8+\n                    <jats:italic>T<\/jats:italic>\n                    cells, evidenced by diminished CD69\n                    <jats:sup>+<\/jats:sup>\n                    \/CD25\n                    <jats:sup>+<\/jats:sup>\n                    surface expression and reduced cytotoxic efficiency. Notably,\n                    <jats:italic>B2M<\/jats:italic>\n                    ablation abolished IFN-\u03b3-induced PD-L1 upregulation (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0&lt;\u00a00.05), demonstrating that intact MHC-I functionality is a prerequisite for PD-L1 expression. Further co-culture systems with PD-1 blockade validated the functional roles of MHC-I and PD-L1 in modulating PD-1 inhibitor resistance mediated by\n                    <jats:italic>B2M<\/jats:italic>\n                    . In conclusion, this work indicated that\n                    <jats:italic>B2M<\/jats:italic>\n                    mutations synergistically drive DLBCL resistance to PD-1 inhibitors through dual mechanisms-suppressing PD-L1 expression and completely disabling antigen presentation. The study highlights that combined strategies restoring MHC-I expression and targeting PD-L1 may overcome immunotherapy resistance, offering a novel direction for precision therapy in DLBCL.\n                  <\/jats:p>","DOI":"10.1515\/biol-2025-1226","type":"journal-article","created":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T04:02:03Z","timestamp":1777176123000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>B2M<\/i>\n                    drives PD-1 inhibitor resistance in DLBCL through independent dual immune escape mechanisms"],"prefix":"10.1515","volume":"21","author":[{"given":"Ying","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Oncology , 3201 Hospital , Hanzhong 723000 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Hematology , 3201 Hospital , Hanzhong 723000 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengtian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology , 3201 Hospital , Hanzhong 723000 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shangdong","family":"Mou","sequence":"additional","affiliation":[{"name":"Department of Oncology , 3201 Hospital , Hanzhong 723000 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feifei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology , 3201 Hospital , Hanzhong 723000 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhongqiang","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Oncology , 3201 Hospital , Hanzhong 723000 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingjuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology , 3201 Hospital , Hanzhong 723000 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"2026042604015540434_j_biol-2025-1226_ref_001","doi-asserted-by":"crossref","unstructured":"Teras, LR, DeSantis, CE, Cerhan, JR, Morton, LM, Jemal, A, Flowers, CR. 2016 US lymphoid malignancy statistics by world health organization subtypes. 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