Immunotherapy in Myeloproliferative Diseases

Braun, Lukas; Zeiser, Robert

doi:10.3390/cells9061559

Cited by 19 publications

(26 citation statements)

References 211 publications

(291 reference statements)

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“…Clinical studies showed an accumulation of MDSC in the peripheral blood and bone marrow of AML patients at diagnosis, compared with healthy donors [ 145 , 146 , 191 ]. MDSC have also been implicated in AML development from MDS and myeloproliferative neoplasms (MPN), as they were reported to suppress the naturally occurring, effective anti-tumor immune response in MPN and MDS patients [ 192 ]. An in vitro study confirmed a direct interaction between CML cells and MDSC – M-MDSC stimulated proliferation of CML cells in a co-culture with both K562 cells and primary CD34+ cells from the leukemic bone marrow.…”

Section: Mdsc and Macrophages In Myeloid Leukemiasmentioning

confidence: 99%

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Swatler

Turos-Korgul

Kozłowska

et al. 2021

Cancers

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Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously promoting development of immunosuppressive regulatory T cells and suppressive myeloid cells. This facilitates disease progression, spreading of leukemic blasts outside the bone marrow niche and therapy resistance. The following review focuses on main immunosuppressive features of myeloid leukemias. Firstly, factors derived directly from leukemic cells – inhibitory receptors, soluble factors and extracellular vesicles, are described. Further, we outline function, properties and origin of main immunosuppressive cells - regulatory T cells, myeloid derived suppressor cells and macrophages. Finally, we analyze interplay between recovery of effector immunity and therapeutic modalities, such as tyrosine kinase inhibitors and chemotherapy.

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Section: Mdsc and Macrophages In Myeloid Leukemiasmentioning

confidence: 99%

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Swatler

Turos-Korgul

Kozłowska

et al. 2021

Cancers

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“…Likewise, it would be relevant to test a combination of blocking antibodies and agents targeting neoantigens expressed by MPN cells. Indeed, recent studies have shown the existence of specific immunity directed against JAK2V617F - and CALR -mutated cells [ 135 , 136 ], as well as the existence of neoantigens, such as CD123, making it possible to discriminate pathological cell clones [ 143 ]. However, anti-tumor immune responses are silenced by overexpression of the PD-1/PD-L1 pathway.…”

Section: Discussionmentioning

confidence: 99%

“…While JAK2 inhibitors would reduce the inflammatory phenomena associated with MPN, anti-PD-1 immunostimulating antibodies would help restore an effective immune response. Additionally, the growing data on the role of CD123 and the promising results of clinical studies carried out with inhibitors of this molecule (in particular Tagraxofusp, a CD123-directed cytotoxin consisting of the fusion of interleukin-3 with a truncated diphtheria toxin payload) make it a target of choice in the treatment of MPN [143]. The promising results presented during EHA2020 suggest that Tagraxofusp has a clinical benefit with limited risk for MF patients (NCT02268253.6.7.0; source: https://library.ehaweb.org/eha/2020/eha25th/295038/).…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms

Almeida

Regimbeau

Jego

et al. 2020

Cancers

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Myeloproliferative neoplasms (MPN) are a group of clonal disorders that affect hematopoietic stem/progenitor cells. These disorders are often caused by oncogenic driver mutations associated with persistent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. While JAK inhibitors, such as ruxolitinib, reduce MPN-related symptoms in myelofibrosis, they do not influence the underlying cause of the disease and are not curative. Due to these limitations, there is a need for alternative therapeutic strategies and targets. Heat shock proteins (HSPs) are cytoprotective stress-response chaperones involved in protein homeostasis and in many critical pathways, including inflammation. Over the last decade, several research teams have unraveled the mechanistic connection between STAT signaling and several HSPs, showing that HSPs are potential therapeutic targets for MPN. These HSPs include HSP70, HSP90 (chaperoning JAK2) and both HSP110 and HSP27, which are key factors modulating STAT3 phosphorylation status. Like the HSPs, the PD-1/PD-L1 signaling pathway has been widely studied in cancer, but the importance of PD-L1-mediated immune escape in MPN was only recently reported. In this review, we summarize the role of HSPs and PD-1/PD-L1 signaling, the modalities of their experimental blockade, and the effect in MPN. Finally, we discuss the potential of these emerging targeted approaches in MPN therapy.

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“…Interleukin-3 receptor (IL-3R) consists of an alpha chain (CD123) and a common beta chain (CD131) [ 86 , 280 ]. IL-3, a cytokine released by activated T-lymphocytes, binds to CD123 which dimerizes with CD131 to trigger downstream JAK2 signalling pathway [ 280 , 281 ]. CD123 is overexpressed in CD34 + /CD38 − LSCs in AML, but not in normal HSCs [ 282 ].…”

Section: Novel Therapies Targeting Mpn Stem Cells Via Signaling mentioning

confidence: 99%

“…This inactivates elongation factor 2 (EF2), which is responsible for protein synthesis. Thus, the apoptosis of LSC is driven [ 280 ]. Early phase clinical trials performed to evaluate the efficacy of tagraxofusp in advanced MF patients showed promising results [ 249 , 283 ] ( Table 3 ).…”

Section: Novel Therapies Targeting Mpn Stem Cells Via Signaling mentioning

confidence: 99%

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Yung

Lee

Chu

et al. 2021

IJMS

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Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.

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Immunotherapy in Myeloproliferative Diseases

Cited by 19 publications

References 211 publications

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

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