TY - JOUR
T1 - Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma
AU - Perez, Cristina
AU - Botta, Cirino
AU - Zabaleta, Aintzane
AU - Puig, Noemi
AU - Cedena, Maria-Teresa
AU - Goicoechea, Ibai
AU - Alameda, Daniel
AU - José-Eneriz, Edurne San
AU - Merino, Juana
AU - Rodríguez-Otero, Paula
AU - Maia, Catarina
AU - Alignani, Diego
AU - Maiso, Patricia
AU - Manrique, Irene
AU - Lara-Astiaso, David
AU - Vilas-Zornoza, Amaia
AU - Sarvide, Sarai
AU - Riillo, Caterina
AU - Rossi, Marco
AU - Rosiñol, Laura
AU - Oriol, Albert
AU - Blanchard, María-Jesús
AU - Rios, Rafael
AU - Sureda, Anna
AU - Martin, Jesus
AU - Martinez, Rafael
AU - Bargay, Joan
AU - De La Rubia, Javier
AU - Hernandez, Miguel-Teodoro
AU - Martinez-Lopez, Joaquin
AU - Orfao, Alberto
AU - Agirre, Xabier
AU - Prosper, Felipe
AU - Mateos, Maria-Victoria
AU - Lahuerta, Juan-José
AU - Blade, Joan
AU - San-Miguel, Jesús F.
AU - Paiva, Bruno
AU - Espinosa, María Casanova
AU - Zamudio, José Luís Guzman
AU - Herranz, Eduardo Ríos
AU - Tamayo, Rafael Rios
AU - Sánchez, Jesús Martín
AU - Bernal, Luís Palomera
AU - Rodríguez, Ana Pilar González
AU - García, María Esther González
AU - Mayol, Antonia Sampol
AU - Lleonart, Joan Bargay
AU - Suárez, Alexia
AU - García, Miguel Teodoro Hernández
AU - Gaisán, Carmen Montes
AU - Ruiz, Belén Hernández
AU - Montero, Felipe Casado
AU - De Miguel Llorente, Dunia
AU - Ramos, Fernando Solano
AU - Garcia, Angela Ibañez
AU - Manteca, Mariví Mateos
AU - Martín, José Mariano Hernández
AU - Barrigón, Fernando Escalante
AU - Frade, Javier García
AU - De Coca, Alfonso García
AU - Franco, Carlos Aguilar
AU - Gómez, Jorge Labrador
AU - Pérez, Elena Cabezudo
AU - Creixentí, Joan Bladé
AU - Balari, Ana María Sureda
AU - Montes, Yolanda González
AU - Teigell, Lourdes Escoda
AU - Guiñón, Antonio García
AU - Monreal, Eugenia Abella
AU - Campos, Juan Alfonso Soler
AU - Tutusaus, Josep María Martí
AU - Rocafiguera, Albert Oriol
AU - Gorrochategui, Miquel Granell
AU - Mesa, Mercedes Gironella
AU - Silva, Carmen Cabrera
AU - Pérez, Marta Sonia González
AU - Loureiro, Ana Dios
AU - Sánchez, José Angel Méndez
AU - Irazu, María Josefa Nájera
AU - Párraga, Francisco Javier Peñalver
AU - Palacios, Juan José Lahuerta
AU - Barahona, Pilar Bravo
AU - Rodríguez, Cristina Encinas
AU - Rivas, José Ángel Hernández
AU - De Oteyza, Jaime Pérez
AU - Del Barrio, Rebeca Iglesias
AU - De La Guia, Ana López
AU - Amor, Adrián Alegre
AU - Pareja, Elena Prieto
AU - Castelló, Isabel Krsnik
AU - Rodríguez, María Jesús Blanchard
AU - Martínez, Rafael Martínez
AU - Grau, Rosalía Riaza
AU - Mesa, Eugenio Giménez
AU - Sainz, Elena Ruiz
AU - De Arriba, Felipe
AU - Jiménez, Jose María Moraleda
AU - Romera, Marta
AU - Cardoso, Felipe Prósper
AU - Pérez, José María Arguiñano
AU - Pomposo, María Puente
AU - Persona, Ernesto Pérez
AU - Casasús, Ana Isabel Teruel
AU - García, Paz Ribas
AU - Ramos, Isidro Jarque
AU - Lor, María Blanca Villarrubia
AU - García, Pedro Luis Fernández
AU - Chamorro, Carmen Martínez
PY - 2020
Y1 - 2020
N2 - 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 CD11b1CD142CD151CD331HLADR2 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 5.016), and the cytotoxic potential of T cells engaged by a BCMA3CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P 5.0007). 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.
AB - 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 CD11b1CD142CD151CD331HLADR2 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 5.016), and the cytotoxic potential of T cells engaged by a BCMA3CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P 5.0007). 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.
KW - n/a
KW - n/a
UR - http://hdl.handle.net/10807/306243
U2 - 10.1182/blood.2019004537
DO - 10.1182/blood.2019004537
M3 - Article
SN - 0006-4971
VL - 136
SP - 199
EP - 209
JO - Blood
JF - Blood
ER -