PI3Kδ inhibition reshapes follicular lymphoma–immune microenvironment cross talk and unleashes the activity of venetoclax
Year: 2020
Type: article
Abstract: Despite idelalisib approval in relapsed follicular lymphoma (FL), a complete characterization of the immunomodulatory consequences of phosphatidylinositol 3-kinase δ (PI3Kδ) inhibition, biomarkers of response, and potential combinatorial therapies in FL remain to be established. Using ex vivo cocultures of FL patient biopsies and follicular dendritic cells (FDCs) to mimic the germinal center (n = 42), we uncovered that PI3Kδ inhibition interferes with FDC-induced genes related to angiogenesis, extracellular matrix formation, and transendothelial migration in a subset of FL samples, defining an 18-gene signature fingerprint of idelalisib sensitivity. A common hallmark of idelalisib found in all FL cases was its interference with the CD40/CD40L pathway and induced proliferation, together with the downregulation of proteins crucial for B-T-cell synapses, leading to an inefficient cross talk between FL cells and the supportive T-follicular helper cells (TFH). Moreover, idelalisib downmodulates the chemokine CCL22, hampering the recruitment of TFH and immunosupressive T-regulatory cells to the FL niche, leading to a less supportive and tolerogenic immune microenvironment. Finally, using BH3 profiling, we uncovered that FL-FDC and FL-macrophage cocultures augment tumor addiction to BCL-XL and MCL-1 or BFL-1, respectively, limiting the cytotoxic activity of the BCL-2 inhibitor venetoclax. Idelalisib restored FL dependence on BCL-2 and venetoclax activity. In summary, idelalisib exhibits a patient-dependent activity toward angiogenesis and lymphoma dissemination. In all FL cases, idelalisib exerts a general reshaping of the FL immune microenvironment and restores dependence on BCL-2, predisposing FL to cell death, providing a mechanistic rationale for investigating the combination of PI3Kδ inhibitors and venetoclax in clinical trials.
Source: Blood Advances
Authors: Neus Serrat, Martina Guerrero-Hernández, Alba Matas-Céspedes, Anella Yahiaoui, Juan G. Valero, Ferran Nadeu, Guillem Clot, Miriam Di Re, Marc Corbera-Bellalta, Laura Magnano, Alfredo Rivas-Delgado, Anna Enjuanes, Silvia Beà, Maria C. Cid, Elías Campo, Joan Montero, Daniel J. Hodson, Armando López-Guillermo, Dolors Colomer, Stacey Tannheimer, Patricia Pérez-Galán
Institutions: Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Centro de Investigación Biomédica en Red, Centro de Investigación Biomédica en Red de Cáncer, Gilead Sciences (United States), Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Medical Research Council, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona Institute of Science and Technology, Institute for Bioengineering of Catalonia
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Funder: Medical Research Council
Awards: Joint Wellcome and MRC Centre, ‘Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute’, Identification of oncogenic drivers in aggressive B cell Lymphoma by ribosome profiling and a novel primary human lymphocyte transformation assay, Wellcome Trust MRC Cambridge Stem Cell Institute
OpenAlex ID: W3084200090