Araujo Ayala, FerranDobaño-López, CèliaGarcia Valero, JuanNadeu Prat, FerranGava, FabienFaria, CarlaNorlund, MarineMorin, RenaudBernes-Lasserre, PascaleSerrat Aymerich, NeusPlaya-Albinyana, HeribertGiménez Martínez, RubénCampo Güerri, EliasLagarde, Jean-MichelLópez Guillermo, ArmandoGiné Soca, EvaColomer Pujol, DolorsBezombes, ChristinePérez Galán, Patricia2025-11-122025-11-122023-04-080887-6924https://hdl.handle.net/2445/224323Mantle cell lymphoma (MCL), a rare and aggressive B-cell non-Hodgkin lymphoma, mainly develops in the lymph node (LN) and creates a protective and immunosuppressive niche that facilitates tumor survival, proliferation and chemoresistance. To capture disease heterogeneity and tumor microenvironment (TME) cues, we have developed the first patient-derived MCL spheroids (MCL-PDLS) that recapitulate tumor oncogenic pathways and immune microenvironment in a multiplexed system that allows easy drug screening, including immunotherapies. MCL spheroids, integrated by tumor B cells, monocytes and autologous T-cells self-organize in disc-shaped structures, where B and T-cells maintain viability and proliferate, and monocytes differentiate into M2-like macrophages. RNA-seq analysis demonstrated that tumor cells recapitulate hallmarks of MCL-LN (proliferation, NF-kB and BCR), with T cells exhibiting an exhaustion profile (PD1, TIM-3 and TIGIT). MCL-PDLS reproduces in vivo responses to ibrutinib and demonstrates that combination of ibrutinib with nivolumab (anti-PD1) may be effective in ibrutinib-resistant cases by engaging an immune response with increased interferon gamma and granzyme B release. In conclusion, MCL-PDLS recapitulates specific MCL-LN features and in vivo responses to ibrutinib, representing a robust tool to study MCL interaction with the immune TME and to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches.13 p.application/pdfengcc-by (c) Araujo Ayala, Ferran et al., 2023http://creativecommons.org/licenses/by/4.0/TumorsPatologiaImmunitatAdultsLimfomesTumorsPathologyImmunityAdulthoodLymphomasinfo:eu-repo/semantics/article7567752025-11-12info:eu-repo/semantics/openAccess37031299