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