Monocytic myeloid‐derived suppressor cells as prognostic factor in chronic myeloid leukaemia patients treated with dasatinib

Giallongo, Cesarina; Parrinello, Nunziatina Laura; Cava, Piera La; Camiolo, Giuseppina; Romano, Alessandra; Scalia, Marina; Stagno, Fabio; Palumbo, Giuseppe A.; Avola, Roberto; Volti, Giovanni Li; Tibullo, Daniele; Raimondo, Francesco Di

doi:10.1111/jcmm.13326

Cited by 43 publications

(40 citation statements)

References 33 publications

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“…Tyrosine kinase inhibitors (TKI) also demonstrate differential effects on MDSCs. In chronic myeloid leukemia patients treated with imatinib, nilotinib, or dasatinib, all three TKIs decreased PMN-MDSCs but only dasatinib reduced CD14 + HLA-DR lo/neg monocytes (97). Furthermore, the decline in CD14 + HLA-DR lo/neg monocytes correlated with positive patient molecular responses.…”

Section: Efficacy Of Therapeutic Approaches Targeting Immunosuppressimentioning

confidence: 99%

The CD14+HLA-DRlo/neg Monocyte: An Immunosuppressive Phenotype That Restrains Responses to Cancer Immunotherapy

2019

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Recent successes in cancer immunotherapy have been tempered by sub-optimal clinical responses in the majority of patients. The impaired anti-tumor immune responses observed in these patients are likely a consequence of immune system dysfunction contributed to by a variety of factors that include, but are not limited to, diminished antigen presentation/detection, leukopenia, a coordinated network of immunosuppressive cell surface proteins, cytokines and cellular mediators. Monocytes that have diminished or no HLA-DR expression, called CD14 + HLA-DR lo/neg monocytes, have emerged as important mediators of tumor-induced immunosuppression. These cells have been grouped into a larger class of suppressive cells called myeloid derived suppressor cells (MDSCs) and are commonly referred to as monocytic myeloid derived suppressor cells. CD14 + HLA-DR lo/neg monocytes were first characterized in patients with sepsis and were shown to regulate the transition from the inflammatory state to immune suppression, ultimately leading to immune paralysis. These immunosuppressive monocytes have also recently been shown to negatively affect responses to PD-1 and CTLA-4 checkpoint inhibition, CAR-T cell therapy, cancer vaccines, and hematopoietic stem cell transplantation. Ultimately, the goal is to understand the role of these cells in the context of immunosuppression not only to facilitate the development of targeted therapies to circumvent their effects, but also to potentially use them as a biomarker for understanding disparate responses to immunotherapeutic regimens. Practical aspects to be explored for development of CD14 + HLA-DR lo/neg monocyte detection in patients are the standardization of flow cytometric gating methods to assess HLA-DR expression, an appropriate quantitation method, test sample type, and processing guidances. Once detection methods are established that yield consistently reproducible results, then further progress can be made toward understanding the role of CD14 + HLA-DR lo/neg monocytes in the immunosuppressive state.

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Section: Efficacy Of Therapeutic Approaches Targeting Immunosuppressimentioning

confidence: 99%

The CD14+HLA-DRlo/neg Monocyte: An Immunosuppressive Phenotype That Restrains Responses to Cancer Immunotherapy

2019

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“…The accumulation of MDSCs has been demonstrated in many types of human solid tumors [6]. However, the relevance of this heterogeneous population in hematopoietic malignancies has only recently gained stronger attention [7][8][9][10]. MDSCs are a phenotypically and functionally heterogeneous group of cells.…”

Section: Introductionmentioning

confidence: 99%

Monocytic MDSC as a source of immunosuppressive cytokines in chronic lymphocytic leukemia (CLL) microenvironment

Kowalska

2020

Folia Histochem Cytobiol.

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Introduction. Myeloid derived suppressor cells (MDSCs) are one of the major components of the tumor microenvironment. The accumulation of MDSCs has been demonstrated in many types of human solid tumors. However, the relevance of this heterogeneous population in hematopoietic malignancies has only recently gained stronger attention. MDSCs are a phenotypically and functionally heterogeneous group of cells. The results of recent studies indicate that the immune dysregulation in chronic lymphocytic leukemia (CLL) affects a monocytic MDSC (M-MDSC) subpopulation. This study aimed to analyze the frequency of M-MDSCs with intracellular IL-10 and TGF-b1 expression in newly diagnosed CLL patients. We investigated the potential role of M-MDSCs in CLL by analyzing the level of IL-10 and TGF-b1 expression in circulating M-MDSCs in correlation with clinical and laboratory parameters characterizing disease activity and patients' immune status. Material and methods. Seventy CLL patients and 17 age-matched healthy volunteers were included in this study. Flow cytometric detection of Mo-MDSCs (CD14 + CD11b + CD15-HLA-DR-/low) with intracellular IL-10 and TGF-b1 expression was done. Results. We found a significantly higher median percentage of M-MDSC with IL-10 or TGF-b1 expression in CLL patients than in healthy volunteers. The percentage of M-MDSC with intracellular IL-10 or TGF-b1 expression was significantly lower in CLL patients at stage 0 as compared to the stages I/II and III/IV according to Rai stages. The percentage of M-MDSC with intracellular TGF-b1 expression was significantly higher in ZAP-70-positive and CD38-positive patients compared with ZAP-70-negative and group of CD38-negative ones. There was also a significantly higher percentage of M-MDSC positive for intracellular TGF-b expression in patients carrying the 11q22.3 and/or the 17p13.1 deletion than in patients without these genetic aberrations. The percentage of M-MDSC IL-10-positive and M-MDSC TGF-b1-positive measured at the time of diagnosis was higher in patients requiring therapy as compared to patients without treatment during the observation period. Conclusion. In conclusion, we have shown that an increased percentage of M-MDSC cells producing IL-10 and TGF-b1 in CLL patients may be associated with the suppression of the immune response against CLL. It can be assumed that the increased percentage of M-MDSC with an intracellular expression of IL-10 and TGF-b1 may be used in the future as the factor defining the group of patients with shorter time to onset of treatment.

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“…In addition to Sunitinib, Dasatinib, a broader spectrum TKI, has been shown to target and reduce M-MDSCs in CML patients. In other cancer models, however, while Dasatinib was able to modulate MDSCs, it strongly negatively impaired T cell activity which outweighed its potential use for immunotherapy (50)(51)(52). Promotion of angiogenesis via the release of vascular endothelial growth factor (VEGF) is one mechanism by which MDSCs exert their protumorigenic effects in the TME.…”

Section: Stat3 Stat5 and C/ebpβmentioning

confidence: 99%

Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

Kramer

Abrams

2020

Front. Immunol.

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The immune system plays a critical role in cancer progression and response to therapy. However, the immune system can be compromised during the neoplastic process. Notably, the myeloid lineage, which gives rise to granulocytic cells, including neutrophils, is a well-recognized target of tumor-mediated immune suppression. Ordinarily, granulocytic cells are integral for host defense, but in neoplasia the normal process of granulocyte differentiation (i.e., granulopoiesis) can be impaired leading instead to the formation of granulocytic (or PMN)-myeloid-derived suppressor cells (MDSCs). Such cells comprise various stages of myeloid differentiation and are defined functionally by their highly pro-tumorigenic and immune suppressive activities. Thus, considerable interest has been devoted to impeding the negative contributions of PMN-MDSCs to the antitumor response. Understanding their biology has the potential to unveil novel therapeutic opportunities to hamper PMN-MDSC production in the bone marrow, their mobilization, or their effector functions within the tumor microenvironment and, therefore, bolster anticancer therapies that require a competent myeloid compartment. In this review, we will highlight mechanisms by which the neoplastic process skews granulopoiesis to produce PMN-MDSCs, summarize mechanisms by which they execute their pro-tumorigenic activities and, lastly, underscore strategies to obstruct their role as negative regulators of antitumor immunity.

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Monocytic myeloid‐derived suppressor cells as prognostic factor in chronic myeloid leukaemia patients treated with dasatinib

Cited by 43 publications

References 33 publications

The CD14+HLA-DRlo/neg Monocyte: An Immunosuppressive Phenotype That Restrains Responses to Cancer Immunotherapy

The CD14+HLA-DRlo/neg Monocyte: An Immunosuppressive Phenotype That Restrains Responses to Cancer Immunotherapy

Monocytic MDSC as a source of immunosuppressive cytokines in chronic lymphocytic leukemia (CLL) microenvironment

Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

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