Publicaciones científicas

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

23-abr-2020 | Revista: 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).

(1) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicadas (CIMA), Pamplona, Na, Spain.
(2) "Annunziata" Hospital of Cosenza, Cosenza, Italy.
(3) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicadas (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), Pamplona, Spain.
(4) Hospital Universitario de Salamanca, Salamanca, Spain.
(5) Hospital Universitario 12 de Octubre, Madrid, Spain.
(6) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC number CB16/12/00369 and CB16/12/00489, Pamplona, Pamplona, Spain.
(7) Clinica Universidad de Navarra, Pamplona, Spain.
(8) Center for Applied Medical Research (CIMA), Pamplona, Spain.
(9) University of Navarra, Pamplona, Spain.
(10) Centro de Investigacion Medica Alplicada. Universidad de Navarra., Pamplona, Spain.
(11) Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369, CB16/12/00489, Pamplona, Spain.
(12) Centro de Investigacion Medica Aplicada, Pamplona, Spain.
(13) Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain, pamplona, Spain.
(14) Magna Graecia University, Catanzaro, Italy.
(15) Hospital Clínic, Institut d'investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
(16) ICO - Hosp Germans Trias i Pujol, Badalona, Spain.
(17) Hospital Ramon y Cajal, madrid, Spain.
(18) Hospital Universitario Virgen de las Nieves, Granada, Spain.
(19) Institut Català d'Oncologia, Barcelona, Spain.
(20) Hospital Universitario Virgen del Rocio, Sevilla, Spain.
(21) Hospital Clinico San Carlos, Madrid, Spain.
(22) Hospital Son LLatzer, Palma Mallorca, Spain.
(23) School of Medicine and Dentistry, Catholic University of Valencia, Spain.
(24) Hospital Universitario de Canarias, La Laguna. Tenerife, Spain.
(25) University of Salamanca, Salamanca, Spain.
(26) Universidad de Navarra, Pamplona, Spain.
(27) University Hospital of Salamanca/IBSAL/Cancer Research Center, Salamanca, Spain.
(28) Hospital Clínic i Provincial, Institut de Investicacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.


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