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Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma

AuthorsPerez, Cristina; Puig, Noemi; Cedena, Maria-Teresa; Alameda, Daniel; Merino, Juana; Rodríguez-Otero, Paula; Maia, Catarina; Alignani, Diego; Maiso, Patricia; Rosiñol, Laura; Oriol, Albert; Blanchard, María Jesús; Ríos, Rafael; Sureda, Anna; Martín, Jesús; Martínez, Rafael; Bargay, Joan; Rubia, Javier de la; Hernandez, Miguel T.; Martínez-López, Joaquín; Orfao, Alberto CSIC ORCID ; Agirre, Xavier; Prósper, Felipe; Lahuerta, Juan José; Bladé, Joan; San Miguel, Jesús F. CSIC ORCID
Issue Date9-Jul-2020
PublisherAmerican Society of Hematolgy
CitationBlood 136(2): 199–209 (2020)
AbstractGranulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14−CD15+CD33+HLADR− cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC–related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
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