PMN-MDSC and arginase are increased in myeloma and may contribute to resistance to therapy

Romano, Alessandra; Parrinello, Nunziatina Laura; Cava, Piera La; Tibullo, Daniele; Giallongo, Cesarina; Camiolo, Giuseppina; Puglisi, Fabrizio; Parisi, Maria Giovanna; Pirosa, Maria Cristina; Martino, Enrica Antonia; Conticello, Concetta; Palumbo, Giuseppe A.; Raimondo, Francesco Di

doi:10.1080/14737159.2018.1470929

Cited by 62 publications

(62 citation statements)

References 34 publications

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“…Revealing the complex immunological dysregulation in MM, the neutrophil-to-lymphocyte ratio at diagnosis or after 100 days from autologous stem cell transplantation can predict outcome in MM patients, even if the novel agents era [16][17][18][19][20][21][22] In cancer, neutrophils can integrate the environmental signals towards an adaptive response to the tumor-associated sterile inflammation, generally associated to a pro-tumoral phenotype 13,[23][24][25][26] . Defects in neutrophil maturation, including reduced lysozyme activity 27 and increased expression of arginase 28,29 , have been described in MM as consequence of the infiltration of the bone marrow by neoplastic cells 27 , but little is known about the contribution of human HDNs in progression from MGUS to MM.…”

Section: To Understand Neutrophil Impairment In the Progression From mentioning

confidence: 99%

“…We found ARG1 gene upregulation among the up-regulated genes in MM-HDNs compared to healthy HDNs. Since our previous work showed that ARG1, a transcriptional target of STAT-3 47,48 , STAT-5 49 and STAT-6 50,51 , is increased in granulocytic-like myeloid derived suppressor cells in MM 28,38,52 , associated to inferior outcome after bortezomib treatment 28 , we explored its expression in both MGUS-and MM-HDNs.…”

Section: Arg-1 Target Of Stat-3 Stat-5 and Stat-6 Is Increased In mentioning

confidence: 99%

“…Overall survival (OS) was defined as time from the date of initial diagnosis to the date of death for any reason or last follow-up. Follow-up times were described as medians by using the inverse Kaplan-Meier estimator [28]. Survival curves were obtained by using the Kaplan-Meier method and were compared with the log-rank test.…”

Section: Quantification Of Phagocytosis and Oxidative Burst Phagocytmentioning

confidence: 99%

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

Romano

Parrinello

Simeon

et al. 2020

Sci Rep

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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.

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Section: To Understand Neutrophil Impairment In the Progression From mentioning

confidence: 99%

Section: Arg-1 Target Of Stat-3 Stat-5 and Stat-6 Is Increased In mentioning

confidence: 99%

Section: Quantification Of Phagocytosis and Oxidative Burst Phagocytmentioning

confidence: 99%

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

Romano

Parrinello

Simeon

et al. 2020

Sci Rep

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“…Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells showing suppressor activity on T cell response that expands during cancer, inflammation, and infection [109]. The increase of CD14 + /HLA-DR −/low MDSCs in newly diagnosed MM patients and during the active/advanced phase of the disease have been reported [110,111]. Arginase-1 (Arg-1) is the principal mediator of the suppressive function of MDSCs [112].…”

Section: Immune Cellsmentioning

confidence: 99%

“…Arginase-1 (Arg-1) is the principal mediator of the suppressive function of MDSCs [112]. Arg-1 depletes the extracellular matrix of the essential amino acid, arginine [112], and directly promotes MM progression and plasma cell resistance to therapy [111]. The inducible isoform of NOS (iNOS) is also induced by MDSCs [112].…”

Section: Immune Cellsmentioning

confidence: 99%

Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma

Ria

Vacca

2020

IJMS

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Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of microenvironment influence many biological aspects of the malignant phenotype, including apoptosis, survival, proliferation, and invasion. Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodies), there is improvement in patient survival, and multiple myeloma (MM) remains a non-curable disease. The bone marrow microenvironment is a complex structure composed of cells, extracellular matrix (ECM) proteins, and cytokines, in which tumor plasma cells home and expand. The role of the bone marrow (BM) microenvironment is fundamental during MM disease progression because modification induced by tumor plasma cells is crucial for composing a “permissive” environment that supports MM plasma cells proliferation, migration, survival, and drug resistance. The “activated phenotype” of the microenvironment of multiple myeloma is functional to plasma cell proliferation and spreading and to plasma cell drug resistance. Plasma cell drug resistance induced by bone marrow stromal cells is mediated by stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs dysregulation. These processes represent novel targets for the ever-increasing anti-MM therapeutic armamentarium.

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Bypassing the Immunosuppression of Myeloid‐Derived Suppressor Cells by Reversing Tumor Hypoxia Using a Platelet‐Inspired Platform

Zhang

Xia

Liu

et al. 2020

Adv Funct Materials

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Myeloid-derived suppressor cells (MDSCs) are garnering increasing attention given their role in tumor development. Herein, a nano-enabled strategy is demonstrated for the eradication of tumor-infiltrated MDSCs by reversing hypoxia. Oxygen-independent photodynamic bismuth tungstate nanoparticles (Bi 2 WO 6 NPs) are loaded into reactive oxygen species (ROS) responsive platelet membranes (PMs) to form a hybrid (PM-BiW NPs). P-Selectin on PMs endows PM-BiW NPs with selectivity toward cancer cells. Once in the tumor, laser illumination stimulates the Bi 2 WO 6 NPs photothermally and photodynamically, which produces enormous quantities of hydroxyl radicals. These hydroxyl radicals help rupture the PM and mitigate hypoxia with the assistance of ionizing radiation. This effectively remodels the tumor micro environment toward one disfavoring the recruitment of MDSCs and contributes to better prognosis. To better understand the mechanism, the expression levels of a set of markers are monitored. It is found that the downregulations of hypoxia-inducible factor-1α, ectonucleoside triphosphate diphosphohydrolase 2, and adenosine-5-phosphoricacid are behind the blocked infiltration of MDSCs. This platform strategy offers a promising approach to overcome the immunosuppression caused by MDSCs through a trimodal therapy integrating the power of photothermal and photodynamic therapy in addition to radiation therapy. Scheme 1. Working principle of PM-BiW NPs. In radical-free RT treatment, oxygen is essential for reaction with the broken end of DNA to augment the damage to an extent beyond the cells' repairing power. This leads to a deteriorated hypoxia condition that helps to recruit MDSCs and inhibits the function of CTLs. For PTT/PDT/RT treatment, in the presence of PM-BiW • OH radicals generated upon illumination can cause the destruction of ROS-responsive PM, followed by their release into cytosol where they behave as a sensitizer for irradiation. As the generation of • OH is fueled by H 2 O, there is no longer oxygen consumption. Thus, the tumor microenvironment is remodeled in such a way that the recruitment of MDSCs is disfavored. This also helps the CTLs respond to stress condition to act effectively against tumors.www.afm-journal.de www.advancedsciencenews.com (3 of 18)

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PMN-MDSC and arginase are increased in myeloma and may contribute to resistance to therapy

Abstract: In MM, Arg-1 is mainly expressed by PMN-MDSC. PMN-MDSC and Arg-1 are reduced in vivo after lenalidomide but not bortezomib treatment.

Cited by 62 publications

References 34 publications

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

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

Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma

Bypassing the Immunosuppression of Myeloid‐Derived Suppressor Cells by Reversing Tumor Hypoxia Using a Platelet‐Inspired Platform

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