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We conducted the first trial of immunotherapy rituximab plus lenalidomide in newly diagnosed FL in China (NCT03715309). One-hundred and fifteen patients were enrolled and treated with rituximab 375\u2009mg\/m\n                    <jats:sup>2<\/jats:sup>\n                    intravenously on day 0 and lenalidomide 25\u2009mg orally on day 1\u201310 for 6 cycles of induction treatment, as well as lenalidomide for 6 cycles and rituximab for 8 cycles of maintenance treatment. We found that inferior progression-free survival of the patients was significantly associated with elevated serum \u03b22m and lymph node &gt;6\u2009cm, linking to decreased lymphoma cell autophagy and dendritic cell infiltration within the tumor microenvironment. PU.1 transcriptionally downregulated PD-L1 (Programmed death ligand 1) expression and upregulated 4-1BBL (4-1BB ligand) expression, increased lymphoma cell autophagy and dendritic cell maturation via PD-1\/PD-L1 and 4-1BB\/4-1BBL interaction. In vitro in co-culture system and in vivo in murine xenograft model, knockdown of PU.1 induced lenalidomide resistance, but sensitized FL cells to bi-specific PD-L1\/4-1BB antibody or combined treatment of PD-L1 inhibitor and 4-1BB agonist. Collectively, PU.1 is essential in immunomodulatory effect of FL through PD-1\/PD-L1- and 4-1BB\/4-1BBL-mediated microenvironmental modulation. Dual targeting PD-L1 and 4-1BB could be an alternative immunotherapeutic strategy in the chemo-free era of FL treatment.\n                  <\/jats:p>","DOI":"10.1038\/s41392-024-02105-7","type":"journal-article","created":{"date-parts":[[2025,1,19]],"date-time":"2025-01-19T18:03:16Z","timestamp":1737309796000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma"],"prefix":"10.1038","volume":"10","author":[{"given":"Zhong","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Biao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Qin","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Yuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Peng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2667-9587","authenticated-orcid":false,"given":"Chuan-Xin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6834-1616","authenticated-orcid":false,"given":"Wei-Li","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,20]]},"reference":[{"key":"2105_CR1","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1182\/blood-2018-08-822148","volume":"133","author":"C Casulo","year":"2019","unstructured":"Casulo, C. & Barr, P. 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