{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:39:48Z","timestamp":1790739588862,"version":"4.1.0"},"reference-count":47,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2023,10,29]],"date-time":"2023-10-29T00:00:00Z","timestamp":1698537600000},"content-version":"unspecified","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"POCTEFA","award":["IMLINFO\/EFA281\/16"],"award-info":[{"award-number":["IMLINFO\/EFA281\/16"]}]},{"DOI":"10.13039\/501100001677","name":"INSERM","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]},{"name":"CALYM Carnot Institute","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100004100","name":"LabEx","doi-asserted-by":"crossref","award":["TOUCAN, G20000BB"],"award-info":[{"award-number":["TOUCAN, G20000BB"]}],"id":[{"id":"10.13039\/501100004100","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Institut Claudius Regaud CLCC","award":["CIEL, R20027BB"],"award-info":[{"award-number":["CIEL, R20027BB"]}]},{"name":"CNRS","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Universit\u00e9 Paul Sabatier","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"personal FPI fellowship from the Ministry of Economy and competitiveness","award":["PRE2018-083797"],"award-info":[{"award-number":["PRE2018-083797"]}]},{"DOI":"10.13039\/501100003329","name":"Ministerio de Economia y Competitividad","doi-asserted-by":"crossref","award":["project SAF2017-88275-R"],"award-info":[{"award-number":["project SAF2017-88275-R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,10,4]]},"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Follicular lymphoma (FL), the most common indolent non-Hodgkin\u2019s Lymphoma, is a heterogeneous disease and a paradigm of the contribution of immune tumor microenvironment to disease onset, progression, and therapy resistance. Patient-derived models are scarce and fail to reproduce immune phenotypes and therapeutic responses.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>To capture disease heterogeneity and microenvironment cues, we developed a patient-derived lymphoma spheroid (FL-PDLS) model culturing FL cells from lymph nodes (LN) with an optimized cytokine cocktail that mimics LN stimuli and maintains tumor cell viability.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>FL-PDLS, mainly composed of tumor B cells (60% on average) and autologous T cells (13%\u2009CD4 and 3%\u2009CD8 on average, respectively), rapidly organizes into patient-specific three-dimensional (3D) structures of three different morphotypes according to 3D imaging analysis. RNAseq analysis indicates that FL-PDLS reproduces FL hallmarks with the overexpression of cell cycle, BCR, or mTOR signaling related gene sets. FL-PDLS also recapitulates the exhausted immune phenotype typical of FL-LN, including expression of BTLA, TIGIT, PD-1, TIM-3, CD39 and CD73 on CD3<jats:sup>+<\/jats:sup> T cells. These features render FL-PDLS an amenable system for immunotherapy testing. With this aim, we demonstrate that the combination of obinutuzumab (anti-CD20) and nivolumab (anti-PD1) reduces tumor load in a significant proportion of FL-PDLS. Interestingly, B cell depletion inversely correlates with the percentage of CD8<jats:sup>+<\/jats:sup> cells positive for PD-1 and TIM-3.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In summary, FL-PDLS is a robust patient-derived 3D system that can be used as a tool to mimic FL pathology and to test novel immunotherapeutic approaches in a context of personalized medicine.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2023-007156","type":"journal-article","created":{"date-parts":[[2023,10,29]],"date-time":"2023-10-29T21:17:16Z","timestamp":1698614236000},"page":"e007156","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Patient-derived lymphoma spheroids integrating immune tumor microenvironment as preclinical follicular lymphoma models for personalized medicine"],"prefix":"10.1136","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9537-4758","authenticated-orcid":false,"given":"Carla","family":"Faria","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Toulouse, Inserm, CNRS, Universit\u00e9 Toulouse III-Paul Sabatier, Centre de Recherches en Canc\u00e9rologie de Toulouse, Toulouse, France"},{"name":"IUCT-Oncopole, Toulouse, France"},{"name":"Laboratoire d\u2019Excellence 'TOUCAN-2', Toulouse, France"},{"name":"Institut Carnot Lymphome CALYM, Pierre-B\u00e9nite, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1255-6121","authenticated-orcid":false,"given":"Fabien","family":"Gava","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Toulouse, Inserm, CNRS, Universit\u00e9 Toulouse III-Paul Sabatier, Centre de Recherches en Canc\u00e9rologie de Toulouse, Toulouse, France"},{"name":"IUCT-Oncopole, Toulouse, France"},{"name":"Laboratoire 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Garcia","family":"Valero","sequence":"additional","affiliation":[{"name":"Department of Hemato-Oncology, IDIBAPS, Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red-Oncolog\u00eda (CIBERONC), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9248-9883","authenticated-orcid":false,"given":"Celia","family":"Doba\u00f1o-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Department of Hemato-Oncology, IDIBAPS, Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red-Oncolog\u00eda (CIBERONC), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0420-5081","authenticated-orcid":false,"given":"Nathalie","family":"Van Acker","sequence":"additional","affiliation":[{"name":"Department of Pathology, Institut Universitaire du Cancer de Toulouse, CHU Toulouse, Toulouse, France"},{"name":"Imag\u2019IN Platform, Institut 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