Scientific publications

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

Apr 23, 2020 | Magazine: Blood

Perez C (1), Botta C (2), Zabaleta A (3), Puig N (4), Cedena MT (5), Goicoechea I (6), Alameda D (7), San-José Enériz E (8), Merino J (9), Rodriguez-Otero P (7), Maia CADS (6), Alignani D (10), Maiso P (7), Manrique I (11), Lara-Astiaso D (11), Vilas-Zornoza A (12), Sarvide S (13), Riillo C (14), Rossi M (14), Rosiñol L (15) Oriol A (16), Blanchard MJ (17), Rios R (18), Sureda A (19), Martín Sánchez J (20), Martinez R (21), Bargay J (22), de la Rubia J (23), Hernandez Garcia MT (24), Martínez-López J (5), Orfao A (25), Agirre X (26), Prosper F (7), Mateos MV (27), Lahuerta JJ (5), Bladé J (28), San Miguel J (26), Paiva B (7).

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 and clinical translation. Here, we aimed at providing the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program.

The pre-established phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry and, surprisingly, we found that CD11b+CD14-CD15+CD33+HLADR- cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients.

Thus, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, 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 patients' outcome, and a high mature-neutrophils/T-cell ratio resulted in inferior progression-free survival (P<.001).

Upon FACSorting of each neutrophil subset, T cell proliferation decreased in presence of mature neutrophils (0.5-fold; P=.016) and the cytotoxic potential of T cells engaged by a BCMAxCD3 bispecific antibody increased notably with the depletion of mature neutrophils (4-fold; P=.0007). Most interestingly, RNAseq of the three subsets revealed that G-MDSCs-related genes were specifically upregulated in mature neutrophils from MM patients vs controls due to differential chromatin accessibility.

Taken together, we established 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-MDCSs in MM.

CITA DEL ARTÍCULO  Blood. 2020 Apr 23. pii: blood.2019004537. doi: 10.1182/blood.2019004537

Our authors

Investigadora predoctoral del Grupo de Mieloma Múltiple del Cima Universidad de Navarra
Dr. Cristina Pérez Ruiz
Dr. Aintzane Zabaleta Azpiroz
Research Associate Multiple Myeloma Research Group
Investigador postdoctoral del Grupo de Mieloma múltiple del Cima Universidad de Navarra
Ibai Goicoechea Oroz
Dr. Edurne San José Enériz
Sarai Sarvide Plano
Laboratory technician Multiple Myeloma Research Group