Patient-derived follicular lymphoma spheroids recapitulate lymph node signaling and immune profile uncovering galectin-9 as a novel immunotherapeutic target

• Published in: Blood cancer journal (New York) Vol. 14; no. 1; pp. 75 - 14
• Main Authors: Dobaño-López, Cèlia, Valero, Juan García, Araujo-Ayala, Ferran, Nadeu, Ferran, Gava, Fabien, Faria, Carla, Norlund, Marine, Morin, Renaud, Bernes-Lasserre, Pascale, Arenas, Fabian, Grau, Marta, López, Cristina, López-Oreja, Irene, Serrat, Neus, Martínez-Farran, Ares, Hernández, Lluís, Playa-Albinyana, Heribert, Giménez, Rubén, Beà, Silvia, Campo, Elías, Lagarde, Jean-Michel, López-Guillermo, Armando, Magnano, Laura, Colomer, Dolors, Bezombes, Christine, Pérez-Galán, Patricia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.05.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/21; 13/31; 14/19; 14/34; 38/32; 38/91; 631/67/1990/291/1621/1915; 692/699/67/1059/2325; Biomedical and Life Sciences; Biomedicine; Cancer Research; Galectins; Hematology; Humans; Immunotherapy - methods; Life Sciences; Lymph Nodes - immunology; Lymph Nodes - pathology; Lymphoma; Lymphoma, Follicular - immunology; Lymphoma, Follicular - pathology; Lymphoma, Follicular - therapy; Oncology; Signal Transduction; Spheroids, Cellular; Tumor Cells, Cultured; Tumor Microenvironment - immunology
• ISSN: 2044-5385; 2044-5385
• DOI: 10.1038/s41408-024-01041-7

Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, constitutes a paradigm of immune tumor microenvironment (TME) contribution to disease onset, progression, and heterogenous clinical outcome. Here we present the first FL-Patient Derived Lymphoma Spheroid (FL-PDLS), including fundamental immune actors and features of TME in FL lymph nodes (LNs). FL-PDLS is organized in disc-shaped 3D structures composed of proliferating B and T cells, together with macrophages with an intermediate M1/M2 phenotype. FL-PDLS recapitulates the most relevant B-cell transcriptional pathways present in FL-LN (proliferation, epigenetic regulation, mTOR, adaptive immune system, among others). The T cell compartment in the FL-PDLS preserves CD4 subsets (follicular helper, regulatory, and follicular regulatory), also encompassing the spectrum of activation/exhaustion phenotypes in CD4 and CD8 populations. Moreover, this system is suitable for chemo and immunotherapy testing, recapitulating results obtained in the clinic. FL-PDLS allowed uncovering that soluble galectin-9 limits rituximab, rituximab, plus nivolumab/TIM-3 antitumoral activities. Blocking galectin-9 improves rituximab efficacy, highlighting galectin-9 as a novel immunotherapeutic target in FL. In conclusion, FL-PDLS maintains the crosstalk between malignant B cells and the immune LN-TME and constitutes a robust and multiplexed pre-clinical tool to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches.