High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling

Abstract

To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.

What Is the Evolutionary Fingerprint in Neutrophil Granulocytes?

“…As the resulting immune-suppression by HNDs is not present in according murine models, a difference in cancer-related myelopoiesis between these species was suggested. Thus, also HDNs are able to support tumor progression and susceptibility to infections at least in human multiple myeloma [209]. In addition, the group of G-MDSCs is composed of various subsets in the tumor microenvironment of multiple myeloma patients: eosinophils, basophils, and three neutrophil maturation stages.…”

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

“…Multiple Myeloma (MM) is a neoplastic plasma cell disorder characterized by a complex array of clinical manifestations, including hypercalcemia, renal dysfunction, anemia, and bone lesions (collectively known as CRAB symptoms), in a wide spectrum of clinical variants ranging from benign MGUS and smoldering/indolent MM, to more aggressive, disseminated forms of MM and plasma cell leukemia ( 124 ). There is no a unique driver genetic event in MM onset, but a complex variety of chromosomal and genomic rearrangements ( 125 ), occurring at different timepoints in response to external driving forces (e.g., exposure to microbes, chronic antigen stimulation, oxidative stress).…”

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

“…Correspondingly, the inhibition of CD16b using CD16 F(ab’)2 did not potentiate ADCC and trogocytosis by these activated neutrophils. Such upregulation of CD64 and downregulation of CD16 has also been observed on HDNs isolated from patients with multiple myeloma [ 115 ]. However, although CD64 is an activating FcR, these HDNs from myeloma patients were less effective in phagocytosis compared to healthy controls, which was caused by the increased expression of arginase-1, which is an enzyme that is immune inhibitory.…”

“…However, although CD64 is an activating FcR, these HDNs from myeloma patients were less effective in phagocytosis compared to healthy controls, which was caused by the increased expression of arginase-1, which is an enzyme that is immune inhibitory. Indeed, arginase-1 inhibitors reactivated the HDNs of myeloma patients [ 115 ]. Reversely, the immunosuppressive cytokine TGF-β may in the tumor microenvironment downregulate CD64 expression, as for instance reported for monocytes [ 116 ].…”