title: Rational targeted therapies to overcome microenvironment-dependent expansion of mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) accumulates in lymphoid organs, but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support their proliferation. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (insulin-like growth factor-1, B-cell activating factor, interleukin-6, interleukin-10). Of interest, we showed that our model recapitulated the MCL in situ molecular signatures (ie, proliferation, NF-κB, and survival signatures). We further demonstrated that proliferating MCL harbored an imbalance in Bcl-2 family expression, leading to a consequent loss of mitochondrial priming. Of interest, this loss of priming was overcome by the type II anti-CD20 antibody obinutuzumab, which counteracted Bcl-xLinduction through NF-κB inhibition. Finally, we showed that the mitochondrial priming directly correlated with the sensitivity toward venetoclax and alkylating drugs. By identifying the microenvironment as the major support for proliferation and drug resistance in MCL, our results highlight a selective approach to target the lymphoma niche.
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Groupement De Recherche 3697 Micronit, CNRS, Tours, France.
authors.forename: David
authors.initials: D
authors.lastname: Chiron
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Groupement De Recherche 3697 Micronit, CNRS, Tours, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Bellanger
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Groupement De Recherche 3697 Micronit, CNRS, Tours, France.
authors.forename: Antonin
authors.initials: A
authors.lastname: Papin
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Groupement De Recherche 3697 Micronit, CNRS, Tours, France.|Service d'Hématologie Clinique, Unité d'Investigation Clinique.
authors.forename: Benoit
authors.initials: B
authors.lastname: Tessoulin
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Groupement De Recherche 3697 Micronit, CNRS, Tours, France.|Centre d'Investigation Clinique, INSERM.
authors.forename: Christelle
authors.initials: C
authors.lastname: Dousset
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Groupement De Recherche 3697 Micronit, CNRS, Tours, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Maiga
authors.affiliation: Service d'Anatomie Pathologique, and.
authors.forename: Anne
authors.initials: A
authors.lastname: Moreau
authors.affiliation: Service de Gynécologie et Obstétrique, Centre Hospitalier Universitaire, Nantes, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Esbelin
authors.affiliation: Groupement De Recherche 3697 Micronit, CNRS, Tours, France.|Laboratoire de Physiopathologie de la Résorption Osseuse, INSERM, Université de Nantes, Nantes, France; and.
authors.forename: Valérie
authors.initials: V
authors.lastname: Trichet
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, NY.
authors.forename: Selina
authors.initials: S
authors.lastname: Chen-Kiang
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Service d'Hématologie Clinique, Unité d'Investigation Clinique.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Service d'Hématologie Clinique, Unité d'Investigation Clinique.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Touzeau
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Groupement De Recherche 3697 Micronit, CNRS, Tours, France.|Service d'Hématologie Clinique, Unité d'Investigation Clinique.
authors.forename: Steven
authors.initials: S
authors.lastname: Le Gouill
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Groupement De Recherche 3697 Micronit, CNRS, Tours, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Amiot
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes, France.|Groupement De Recherche 3697 Micronit, CNRS, Tours, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pellat-Deceunynck
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D018951:Antigens, CD20 / Q000276:immunology; D023201:CD40 Ligand / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008221:Lymphoid Tissue / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000473:pathology* / Q000628:therapy*; D008297:Male; D008648:Mesoderm / Q000473:pathology; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D051020:bcl-X Protein; D023201:CD40 Ligand; C543332:obinutuzumab