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

Abstract

<jats:title>Abstract</jats:title> <jats:p>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 CD11b+CD14−CD15+CD33+HLADR− 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 &amp;lt; .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .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.</jats:p>

Treatment of Lenalidomide Exposed or Refractory Multiple Myeloma: Network Meta-Analysis of Lenalidomide-Sparing Regimens

“…Along the same line, the efficacy of the new pomalidomide/mAbs combo regimens, which look very promising, could not be evaluated with this approach, mainly due to the fact that all the investigational clinical trials have been performed in more advanced settings (from the third line of therapy) by using (always) PD as control arm (12)(13)(14). Translational investigations, which shed light on the biologic interplay which take place within the bone marrow microenvironment (15)(16)(17)(18)(19) are eagerly awaited and could help to develop new therapeutic approaches in this setting. Finally, this work should be considered a snapshot of current evidence, taking into account that some of these drugs will probably move to the frontline setting.…”

What Is the Evolutionary Fingerprint in Neutrophil Granulocytes?

“…The pro-tumorigenic response goes along with induced transcription of inflammatory signals and an inhibiting effect on T-cells. This is due to a molecular reprogramming of the mature neutrophils, probably influenced by TGF-β [211]. Another mechanism involved in tumor progression is autophagy, leading to cell survival under stress conditions if upregulated in neutrophils [206,212].…”

“…Thus, for instance CD8 T-cells are induced to undergo apoptosis and limited in their proliferation [221]. The mature population of G-MDSCs also decreases the cytotoxicity of T-cells [211]. On the other hand, TANs can also act tumor-suppressive by influencing T-cells.…”

The Neutrophil: The Underdog That Packs a Punch in the Fight against Cancer

“…Furthermore, in co-cultures with neutrophils, CD3/CD28-activated T cells differentiated more into a “central memory” phenotype, increasing from 19% in CD8 + monocultures to 45% in CD8 + co-cultured with neutrophils, which is a phenotype essential for anticancer immune responses [ 228 ]. In contrast to the above, mature neutrophils of multiple myeloma patients significantly decreased T cell proliferation upon triggering the CD3 receptor using a bispecific antibody, which was not observed when using neutrophils from healthy donors [ 229 ]. However, only the level of mature neutrophils, which had increased TGF-β signaling suggesting being N2 neutrophils, correlated with prognosis in these patients.…”