Detalle Publicación

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

Autores: Pérez Ruiz, Cristina; Botta, C.; Zabaleta, A.; Cedena, M. T.; Goicoechea Oroz, Ibai; Alameda Serrano, Daniel; San José Enériz, Edurne; Merino Roncal, Juana María; Rodríguez Otero, Paula; Catarina, M.; Alignani, Diego Oscar; Maiso Castellanos, Patricia; Manrique Sáenz de Tejada, Irene; LARA ASTIASO, David; Vilas Zornoza, Amaia; Sarvide Plano, Sarai; Riillo, C.; Rossi, M.; Rosinol, L.; Oriol, A.; Blanchard, M. J.; Rios, R.; Sureda, A.; Martin, J.; Martinez, R.; Bargay, J.; de la Rubia, J. ; Hernández, M. T.; Martínez-López, J.; Orfao, A.; Aguirre Ena, Xabier; Prosper Cardoso, Felipe; Mateos, M. V.; Lahuerta, J. J.; Blade, J.; San Miguel Izquierdo, Jesús; Paiva, Bruno (Autor de correspondencia)
Título de la revista: BLOOD
ISSN: 0006-4971
Volumen: 136
Número: 2
Páginas: 199 - 209
Fecha de publicación: 2020
Granulocytic 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.