Details

Autor(en) / Beteiligte

• Perez, Cristina
• Botta, Cirino
• Zabaleta, Aintzane
• Puig, Noemi
• Cedena, Maria-Teresa
• Goicoechea, Ibai
• Alameda, Daniel
• San José-Eneriz, Edurne
• Merino, Juana
• Rodríguez-Otero, Paula
• Maia, Catarina
• Alignani, Diego
• Maiso, Patricia
• Manrique, Irene
• Lara-Astiaso, David
• Vilas-Zornoza, Amaia
• Sarvide, Sarai
• Riillo, Caterina
• Rossi, Marco
• Rosiñol, Laura
• Oriol, Albert
• Blanchard, María-Jesús
• Rios, Rafael
• Sureda, Anna
• Martin, Jesus
• Martinez, Rafael
• Bargay, Joan
• de la Rubia, Javier
• Hernandez, Miguel-Teodoro
• Martinez-Lopez, Joaquin
• Orfao, Alberto
• Agirre, Xabier
• Prosper, Felipe
• Mateos, Maria-Victoria
• Lahuerta, Juan-José
• Blade, Joan
• San-Miguel, Jesús F.
• Paiva, Bruno

Titel

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

Ist Teil von

• Blood, 2020-07, Vol.136 (2), p.199-209

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •There is a progressive gradient of immunosuppression from immature to mature neutrophils present in the myeloma microenvironment.•CD11b+CD13+CD16+ mature neutrophils are epigenetically deregulated, and their abundance in the myeloma microenvironment is prognostic. [Display omitted]