Abstract
BackgroundThe aim of this study is to evaluate the prognostic impact of myeloid-derived suppressor cells (MDSCs) in multiple myeloma (MM) in the context of autologous stem cell transplantation (ASCT).MethodsPeripheral blood samples were collected for measuring monocytic (M-) MDSCs (CD14posHLA-DRlow/neg) and early-stage (E-) MDSCs (LinnegHLA-DRnegCD33posCD11bpos) before and after ASCT. Clinical outcomes following ASCT differed according to the frequency of each MDSC phenotype.ResultsIn the pre-ASCT analyses, lower M-MDSCs (<median) but not E-MDSCs were associated with a longer time to progression (TTP), whereas both MDSC phenotypes post-ASCT did not have a role in TTP. Both MDSC phenotypes pre-ASCT but not post-ASCT similarly suppressed in vitro autologous T and natural killer T cell proliferation. Importantly, pre-ASCT M-MDSCs more strongly inhibited the in vitro cytotoxic effect of melphalan compared with pre-ASCT E-MDSCs. Transcriptome analysis of each isolated MDSC subtype showed that expression of osteoclastic differentiation factors, particularly colony-stimulating factor 1 receptor (CSF1R), was significantly increased in M-MDSCs pre-ASCT. Finally, blockade of CSF1R substantially recovered the melphalan-induced cytotoxicity reduced by pre-ASCT M-MDSCs.ConclusionsOur data demonstrate that pre-ASCT M-MDSCs are correlated with poor clinical outcomes after ASCT through reduced cytotoxicity of melphalan. We propose that targeting CSF1R on these cells may improve the results of ASCT in MM.
Highlights
For over two decades, autologous stem cell transplantation (ASCT) has been the standard consolidation treatment for transplant-eligible patients with newly diagnosed multiple myeloma (MM) to improve depth of response, progression-free survival (PFS), and likely overall survival (OS) [1]
colony-stimulating factor 1 receptor (CSF1R) signalling is critical for attenuation of melphalaninduced cytotoxic effect by pre-ASCT M-myeloid-derived suppressor cells (MDSCs) to determine whether a CSF1R inhibitor can recover melphalan-induced cytotoxicity attenuated by pre-ASCT M-MDSCs, we examined the influence of BLZ945, a human CSF1R inhibitor, on cell death induced by melphalan (Fig. 5a)
Similar results were obtained using the RPMI 8226 and OPM2 cell lines (Additional file 7: Figure S4). These results demonstrate that inhibition of CSF1R signalling results in recovery of anti-MM activity by melphalan, which is attenuated by pre-ASCT M-MDSCs
Summary
Autologous stem cell transplantation (ASCT) has been the standard consolidation treatment for transplant-eligible patients with newly diagnosed multiple myeloma (MM) to improve depth of response, progression-free survival (PFS), and likely overall survival (OS) [1]. Large numbers of myeloid-derived suppressor cells (MDSCs), a mixture of monocytic and granulocytic cells, accumulate during many pathologic conditions, including cancer, infectious diseases, trauma, and sepsis. Lee et al Journal for ImmunoTherapy of Cancer (2019) 7:35 characterized by myeloid origin, immature state, and most importantly by their potent ability to suppress different aspects of immune responses, especially T cell proliferation and cytokine production [7]. Granulocytic MDSCs (G-MDSCs) are defined as lacking expression of CD14 but expressing CD15/CD33/ CD11b, whereas monocytic-MDSCs (M-MDSCs) express CD14/CD11b and are characterized as HLA-DR−/low cells or CD33+ cells [8]. The aim of this study is to evaluate the prognostic impact of myeloid-derived suppressor cells (MDSCs) in multiple myeloma (MM) in the context of autologous stem cell transplantation (ASCT). Clinical outcomes following ASCT differed according to the frequency of each MDSC phenotype
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