{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T06:05:41Z","timestamp":1784786741266,"version":"3.55.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Non-Hodgkin lymphomas (NHL) represent a heterogeneous group of B-cell-derived malignancies. Previous studies showed that tumor immune microenvironment (TIM) components are associated with tumor development and progression. Furthermore, recent transcriptomic analyses revealed that TIM status can stratify patients into distinct prognostic groups; however, these insights are not clinically exploited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We characterized the TIM of 64 NHL biopsies and 16 reactive lymphoid tissues (rLT) controls using multi-parameter flow cytometry, including major subpopulations, T-cell subsets and immune checkpoint expression on healthy\/malignant B and T cells. Individuals were stratified by TIM profiles, and prognostic values were evaluated. The mutational landscape was also assessed by targeted DNA sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Flow cytometry analysis revealed HLA-I downregulation in a patient subset and increased expression of inhibitory ligands, particularly in diffuse large B-cell lymphoma (DLBCL). T cells showed a shift toward effector profiles and higher exhaustion marker expression compared with rLT. TIM composition did not differ substantially between patients with specific mutations. TIM-based clustering identified three distinct groups primarily defined by T-cell exhaustion. We assessed the prognostic impact of TIM classification in follicular lymphoma (FL), the most prevalent diagnosis in our cohort. FL patients in cluster C1, characterized by higher frequencies of CD4\n                      <jats:sup>+<\/jats:sup>\n                      and na\u00efve T cells, showed longer time to treatment, overall survival and progression-free survival outcomes compared with FL cases from cluster C2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The classification of TIM profiles by flow cytometry in NHL patients predicts the outcome of FL patients, highlighting its value for risk stratification and identifying potential immunotherapeutic targets in NHL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1882562","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T05:38:13Z","timestamp":1784785093000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumoral immune microenvironment profiling in B-cell non-Hodgkin lymphoma stratifies patients in different prognostic groups"],"prefix":"10.3389","volume":"17","author":[{"given":"Daniel","family":"Medina-Gil","sequence":"first","affiliation":[{"name":"Experimental Hematology, Vall d\u2019Hebron Institute of Oncology (VHIO), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]},{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor","family":"Navarro","sequence":"additional","affiliation":[{"name":"Statistics Unit, Vall d\u2019Hebron Institute of Oncology (VHIO), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C.","family":"Nieto","sequence":"additional","affiliation":[{"name":"Experimental Hematology, Vall d\u2019Hebron Institute of Oncology (VHIO), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]},{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia","family":"Carabia","sequence":"additional","affiliation":[{"name":"Experimental Hematology, Vall d\u2019Hebron Institute of Oncology (VHIO), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]},{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Palomo","sequence":"additional","affiliation":[{"name":"Experimental Hematology, Vall d\u2019Hebron Institute of Oncology (VHIO), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]},{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carles","family":"Palacio-Garcia","sequence":"additional","affiliation":[{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]},{"name":"Servei d\u2019Hematologia, Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]},{"name":"Servei d\u2019Hematologia, Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlota","family":"Pag\u00e8s-Geli","sequence":"additional","affiliation":[{"name":"Experimental Hematology, Vall d\u2019Hebron Institute of Oncology (VHIO), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]},{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Acha","sequence":"additional","affiliation":[{"name":"Experimental Hematology, Vall d\u2019Hebron Institute of Oncology (VHIO), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]},{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Gallur","sequence":"additional","affiliation":[{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]},{"name":"Servei d\u2019Hematologia, Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Pujadas","sequence":"additional","affiliation":[{"name":"Experimental Hematology, Vall d\u2019Hebron Institute of Oncology (VHIO), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]},{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep","family":"Castellv\u00ed","sequence":"additional","affiliation":[{"name":"Translational Molecular Pathology, Vall d\u2019Hebron Institute of Research (VHIR), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pau","family":"Abrisqueta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]},{"name":"Servei d\u2019Hematologia, Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc","family":"Bosch","sequence":"additional","affiliation":[{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]},{"name":"Servei d\u2019Hematologia, Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Crespo","sequence":"additional","affiliation":[{"name":"Experimental Hematology, Vall d\u2019Hebron Institute of Oncology (VHIO), Instituto de Investigaci\u00f3n Sanitaria Hospital Universitari Vall d\u2019Hebron (IIS IR-HUVH)","place":["Barcelona, Spain"]},{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)02705-8","article-title":"B-cell non-hodgkin lymphomas","volume":"403","author":"Silkenstedt","year":"2024","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/PPO.0000000000000451","article-title":"Lymphoma classification","volume":"26","author":"de Leval","year":"2020","journal-title":"Cancer J"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.15412","article-title":"How I manage patients with relapsed\/refractory diffuse large B cell lymphoma","volume":"182","author":"Gisselbrecht","year":"2018","journal-title":"Br J Haematol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx189","article-title":"Unmet needs in the first-line treatment of follicular lymphoma","volume":"28","author":"Casulo","year":"2017","journal-title":"Ann Oncol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41408-024-00997-w","article-title":"Bispecific antibodies and CAR-T cells: dueling immunotherapies for large B-cell lymphomas","volume":"14","author":"Trabolsi","year":"2024","journal-title":"Blood Cancer J"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.11.006","article-title":"Combined genetic inactivation of \u03b22-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma","volume":"20","author":"Challa-Malladi","year":"2011","journal-title":"Cancer Cell"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0351","article-title":"TIGIT and PD-1 mark intratumoral T cells with reduced effector function in B-cell non-hodgkin lymphoma","volume":"7","author":"Josefsson","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.184192","article-title":"Hide or defend, the two strategies of lymphoma immune evasion: potential implications for immunotherapy","volume":"103","author":"De Charette","year":"2018","journal-title":"Haematologica"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.669474","article-title":"Differentiation and regulation of TH cells: a balancing act for cancer immunotherapy","volume":"12","author":"Basu","year":"2021","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa041869","article-title":"Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells","volume":"351","author":"Dave","year":"2004","journal-title":"N Engl J Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy450","article-title":"Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue","volume":"29","author":"Ciavarella","year":"2018","journal-title":"Ann Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020008119","article-title":"Treatment dependence of prognostic gene expression signatures in de novo follicular lymphoma","volume":"137","author":"Bolen","year":"2021","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-0839","article-title":"Clinical and biological subtypes of B-cell lymphoma revealed by microenvironmental signatures","volume":"11","author":"Kotlov","year":"2021","journal-title":"Cancer Discov"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1016\/j.ccell.2021.08.011","article-title":"The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma","volume":"39","author":"Steen","year":"2021","journal-title":"Cancer Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01358-2","article-title":"Multimodal and spatially resolved profiling identifies distinct patterns of T cell infiltration in nodal B cell lymphoma entities","volume":"26","author":"Roider","year":"2024","journal-title":"Nat Cell Biol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"63","DOI":"10.12688\/f1000research.16665.2","article-title":"Sarek: a portable workflow for whole-genome sequencing analysis of germline and somatic variants","volume":"9","author":"Garcia","year":"2020","journal-title":"F1000Research"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0439-x","article-title":"The nf-core framework for community-curated bioinformatics pipelines","volume":"38","author":"Ewels","year":"2020","journal-title":"Nat Biotechnol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2856","article-title":"Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma","volume":"46","author":"Okosun","year":"2014","journal-title":"Nat Genet"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-07-729954","article-title":"Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma","volume":"129","author":"Krysiak","year":"2017","journal-title":"Blood"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv019","article-title":"Genetic lesions in diffuse large B-cell lymphomas","volume":"26","author":"Testoni","year":"2015","journal-title":"Ann Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801445","article-title":"Genetics and pathogenesis of diffuse large B-cell lymphoma","volume":"378","author":"Schmitz","year":"2018","journal-title":"N Engl J Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1295202","article-title":"HLA dependent immune escape mechanisms in B-cell lymphomas: implications for immune checkpoint inhibitor therapy","volume":"6","author":"Nijland","year":"2017","journal-title":"Oncoimmunology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2104504118","article-title":"Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma","volume":"118","author":"Fangazio","year":"2021","journal-title":"Proc Natl Acad Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-02-629600","article-title":"Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma","volume":"126","author":"Kiyasu","year":"2015","journal-title":"Blood"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/his.12882","article-title":"Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas","volume":"68","author":"Kwon","year":"2016","journal-title":"Histopathology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"33350","DOI":"10.18632\/oncotarget.9061","article-title":"Co-expression of PD-L1 and p-AKT is associated with poor prognosis in diffuse large B-cell lymphoma via PD-1\/PD-L1 axis activating intracellular AKT\/mTOR pathway in tumor cells","volume":"7","author":"Dong","year":"2016","journal-title":"Oncotarget"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-0589","article-title":"Follicular B lymphomas generate regulatory T cells via the ICOS\/ICOSL pathway and are susceptible to treatment by anti-ICOS\/ICOSL therapy","volume":"76","author":"Le","year":"2016","journal-title":"Cancer Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e318268c6ea","article-title":"CD137 ligand is expressed in primary and secondary lymphoid follicles and in B-cell lymphomas: diagnostic and therapeutic implications","volume":"37","author":"Zhao","year":"2013","journal-title":"Am J Surg Pathol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.251","article-title":"Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets","volume":"32","author":"Karube","year":"2018","journal-title":"Leukemia"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59806","article-title":"IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-hodgkin lymphoma","volume":"122","author":"Yang","year":"2012","journal-title":"J Clin Invest"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019001390","article-title":"LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma","volume":"4","author":"Keane","year":"2020","journal-title":"Blood Adv"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-05-223958","article-title":"Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion","volume":"114","author":"Houot","year":"2009","journal-title":"Blood"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-08-105395","article-title":"Local and systemic induction of CD4+ CD25+ regulatory T-cell population by non-hodgkin lymphoma","volume":"111","author":"Mittal","year":"2008","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0010-1","article-title":"Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia","volume":"24","author":"Fraietta","year":"2018","journal-title":"Nat Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.ccell.2023.02.008","article-title":"The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients","volume":"41","author":"Friedrich","year":"2023","journal-title":"Cancer Cell"},{"key":"B37","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/s41408-023-00958-9","article-title":"The intrinsic defects of T cells impact the efficacy of CAR-T therapy in patients with diffuse large B-cell lymphoma","volume":"13","author":"Zhao","year":"2023","journal-title":"Blood Cancer J"},{"key":"B38","doi-asserted-by":"publisher","first-page":"2178","DOI":"10.1016\/j.celrep.2019.01.085","article-title":"Mass cytometry analysis reveals that specific intratumoral CD4+ T cell subsets correlate with patient survival in follicular lymphoma","volume":"26","author":"Yang","year":"2019","journal-title":"Cell Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1882562\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T05:38:14Z","timestamp":1784785094000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1882562\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2026.1882562"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1882562","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]},"article-number":"1882562"}}