A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia

Aru, Başak; Pehlivanoğlu, Cemil; Dal, Zeynep; Dereli-Çalışkan, Nida Nur; Gürlü, Ege; Demirel, Gülderen Yanikkaya

doi:10.3389/fimmu.2023.1108200

Cited by 8 publications

(4 citation statements)

References 196 publications

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“…AML progresses swiftly, presenting a bleak prognosis, its pathogenesis remains elusive [ 23 ]. Contemporary research suggests that the genesis and evolution of AML might intimately correlate with the immune microenvironment within its bone marrow [ 24 ]. This association may extend to AML’s therapeutic responsiveness.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal evolution of AML immune microenvironment remodeling and RNF149-driven drug resistance through single-cell multidimensional analysis

Wu,

Deng

et al. 2023

J Transl Med

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Background The composition of the bone marrow immune microenvironment in patients with acute myeloid leukaemia (AML) was analysed by single-cell sequencing and the evolutionary role of different subpopulations of T cells in the development of AML and in driving drug resistance was explored in conjunction with E3 ubiquitin ligase-related genes. Methods To elucidate the mechanisms underlying AML-NR and Ara-C resistance, we analyzed the bone marrow immune microenvironment of AML patients by integrating multiple single-cell RNA sequencing datasets. When compared to the AML disease remission (AML-CR) cohort, AML-NR displayed distinct cellular interactions and alterations in the ratios of CD4+T, Treg, and CD8+T cell populations. Results Our findings indicate that the E3 ubiquitin ligase RNF149 accelerates AML progression, modifies the AML immune milieu, triggers CD8+T cell dysfunction, and influences the transformation of CD8+ Navie.T cells to CD8+TExh, culminating in diminished AML responsiveness to chemotherapeutic agents. Experiments both in vivo and in vitro revealed RNF149’s role in enhancing AML drug-resistant cell line proliferation and in apoptotic inhibition, fostering resistance to Ara-C. Conclusion In essence, the immune microenvironments of AML-CR and AML-NR diverge considerably, spotlighting RNF149’s tumorigenic function in AML and cementing its status as a potential prognostic indicator and innovative therapeutic avenue for countering AML resistance. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Spatiotemporal evolution of AML immune microenvironment remodeling and RNF149-driven drug resistance through single-cell multidimensional analysis

Wu,

Deng

et al. 2023

J Transl Med

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“…Furthermore, tumor cell-specific expression of VISTA, regulated by the forkhead box D3 (FOXD3) factor, promotes tumorigenesis and enhances PD-L1 expression on tumor-infiltrating macrophages in vivo, which is associated with increased intra-tumoral T regulatory cells [62]. It is worth noting that VISTA exhibits high expression on myeloid-derived suppressor cells in the peripheral blood, and there is a strong positive correlation between MDSC expression of VISTA and T cell expression of PD-1 in patients with AML, although direct regulation has yet to be substantiated [64,65]. MDSCs are myeloid cells that are defined into subsets namely monocytic MDSCs (CD15 − ) and granulocytic MDSCs (CD15 + ) [66].…”

Section: V-domain Immunoglobulin Suppressor Of T Cell Activation (Vis...mentioning

confidence: 99%

Role of Next Generation Immune Checkpoint Inhibitor (ICI) Therapy in Philadelphia Negative Classic Myeloproliferative Neoplasm (MPN): Review of the Literature

Yadav,

Hakobyan,

Wang

2023

IJMS

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The Philadelphia chromosome-negative (Ph−) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body’s stem cells, leading to the enlargement of organs and the manifestation of constitutional symptoms. Numerous studies have provided evidence indicating that the pathogenesis of these diseases involves the dysregulation of the immune system and the presence of chronic inflammation, both of which are significant factors. Lately, the treatment of cancer including hematological malignancy has progressed on the agents aiming for the immune system, cytokine environment, immunotherapy agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cell function in the tumor microenvironment (TME). The first line of primary immune checkpoints are programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) exerts its anti-tumor actions by blocking the inhibitory pathways in T cells and has reformed cancer treatment. Despite the impressive clinical success of ICIT, tumor internal resistance poses a challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A Phase II trial on nivolumab for patients with post-essential thrombocythemia myelofibrosis, primary myelofibrosis, or post-polycythemia myelofibrosis was performed (Identifier: NCT02421354). This trial tested the efficacy of a PD-1 blockade agent, namely nivolumab, but was terminated prematurely due to adverse events and lack of efficacy. A multicenter, Phase II, single-arm open-label study was conducted including pembrolizumab in patients with primary thrombocythemia, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. This study showed that pembrolizumab treatment did not have many adverse events, but there were no pertinent clinical responses hence it was terminated after the first stage was completed. To avail the benefits from immunotherapy, the paradigm has shifted to new immune checkpoints in the TME such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. The primary aim of this article is to underscore and elucidate the significance of next-generation ICIT in the context of MPN. Specifically, we aim to explore the potential of monoclonal antibodies as targeted immunotherapy and the development of vaccines targeting specific MPN epitopes, with the intent of augmenting tumor-related immune responses. It is anticipated that these therapeutic modalities rooted in immunotherapy will not only expand but also enhance the existing treatment regimens for patients afflicted with MPN. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN.

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“… 33 , 34 Targeting signaling molecules are potential therapeutic targets for developing targeted therapies for each type of leukemia. 35 , 36 In this study, we reviewed the cellular pathways involved in the stimulation and prevention of LSCs' self-renewal, metastasis, and tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Signaling pathways governing the behaviors of leukemia stem cells

Azizidoost¹,

Nasrolahi²,

Sheykhi-Sabzehpoush³

et al. 2024

Genes & Diseases

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A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia

Cited by 8 publications

References 196 publications

Spatiotemporal evolution of AML immune microenvironment remodeling and RNF149-driven drug resistance through single-cell multidimensional analysis

Spatiotemporal evolution of AML immune microenvironment remodeling and RNF149-driven drug resistance through single-cell multidimensional analysis

Role of Next Generation Immune Checkpoint Inhibitor (ICI) Therapy in Philadelphia Negative Classic Myeloproliferative Neoplasm (MPN): Review of the Literature

Signaling pathways governing the behaviors of leukemia stem cells

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