Key Points

  • There is a progressive gradient of immunosuppression from immature into mature neutrophils present in the myeloma microenvironment

  • CD11b+CD13+CD16+ mature neutrophils are epigenetically deregulated and their abundance in the myeloma microenvironment is prognostic

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.

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