The Generation and Identity of Human Myeloid-Derived Suppressor Cells

Bergenfelz, Caroline; Leandersson, Karin

doi:10.3389/fonc.2020.00109

Cited by 81 publications

(72 citation statements)

References 114 publications

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“…Tumor-induced immature myeloid cells exhibit considerable heterogeneity and are generally not present in the circulation of healthy persons [36]. Also known as T cell-suppressive neutrophils, these tumor-co-opted MDSCs are predominantly of granulocytic (gMDSCs)/polymorphonuclear leukocyte (PMN-MDSCs) origin [36,51,52]. Although enriched in the so-called low-density neutrophil fraction, they have no recognized distinguishing markers of differentiation, essentially resembling immature neutrophils, both morphologically and phenotypically (CD11b [36,51,52].…”

Section: Myeloid-derived Suppressor Cells (Mdscs)mentioning

confidence: 99%

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

et al. 2020

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Notwithstanding the well-recognized involvement of chronic neutrophilic inflammation in the initiation phase of many types of epithelial cancers, a growing body of evidence has also implicated these cells in the pathogenesis of the later phases of cancer development, specifically progression and spread. In this setting, established tumors have a propensity to induce myelopoiesis and to recruit neutrophils to the tumor microenvironment (TME), where these cells undergo reprogramming and transitioning to myeloid-derived suppressor cells (MDSCs) with a pro-tumorigenic phenotype. In the TME, these MDSCs, via the production of a broad range of mediators, not only attenuate the anti-tumor activity of tumor-infiltrating lymphocytes, but also exclude these cells from the TME. Realization of the pro-tumorigenic activities of MDSCs of neutrophilic origin has resulted in the development of a range of adjunctive strategies targeting the recruitment of these cells and/or the harmful activities of their mediators of immunosuppression. Most of these are in the pre-clinical or very early clinical stages of evaluation. Notable exceptions, however, are several pharmacologic, allosteric inhibitors of neutrophil/MDSC CXCR1/2 receptors. These agents have entered late-stage clinical assessment as adjuncts to either chemotherapy or inhibitory immune checkpoint-targeted therapy in patients with various types of advanced malignancy. The current review updates the origins and identities of MDSCs of neutrophilic origin and their spectrum of immunosuppressive mediators, as well as current and pipeline MDSC-targeted strategies as potential adjuncts to cancer therapies. These sections are preceded by a consideration of the carcinogenic potential of neutrophils.

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Section: Myeloid-derived Suppressor Cells (Mdscs)mentioning

confidence: 99%

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

et al. 2020

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“…Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immunosuppressive myeloid cells developing from myeloid progenitors, which are particularly enriched in pathological conditions such as cancer, infections, inflammation and sepsis [1][2][3]. These pathological conditions determine an increase in circulating colonystimulating factors (CSFs) as well as chemokines that stimulate the myelopoiesis and, consequently, the generation of immature MDSCs.…”

Section: Introductionmentioning

confidence: 99%

Human MDSCs derived from the bone marrow maintain their functional ability but have a reduced frequency of induction in the elderly compared to pediatric donors

et al. 2020

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Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known to inhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses on the role of age-related processes in myelopoiesis.

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“…MDSCs are one of the key types of immunosuppressive cells with heterogeneous cell populations that can be found in tumor-bearing mice and in patients with cancer (Table 1) [6]. In humans, MDSCs are defined by a combination of several surface markers (e.g., CD11b + CD14 − HLA-DR − for monocytic (Mo-)MDSCs, or CD11b + CD14 − CD33 + CD15 + CD66b + for granulocytic (G)MDSCs) [28,29]. Since these markers are also expressed on other immune cells, such as neutrophils (e.g., CD15, CD66b), evaluation of direct immunosuppressive function is mandatory for the definition of MDSCs [28].…”

Section: Significance Of Mdscs In Developing Skin Cancersmentioning

confidence: 99%

“…In humans, MDSCs are defined by a combination of several surface markers (e.g., CD11b + CD14 − HLA-DR − for monocytic (Mo-)MDSCs, or CD11b + CD14 − CD33 + CD15 + CD66b + for granulocytic (G)MDSCs) [28,29]. Since these markers are also expressed on other immune cells, such as neutrophils (e.g., CD15, CD66b), evaluation of direct immunosuppressive function is mandatory for the definition of MDSCs [28]. The immunosuppressive functions of MDSCs are mediated by several secreted factors, including prostaglandin E2 (PGE2), IL-10, transforming growth factor (TGF)-β, nitric oxide (NO) and arginase 1 (Arg1) for Mo-MDSCs [28,30], and reactive oxygen species (ROS), granulocyte-colony stimulating factor (G-CSF) and Arg1 for G-MDSCs [28].…”

Section: Significance Of Mdscs In Developing Skin Cancersmentioning

confidence: 99%

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

Fujimura

Aiba

2020

Biomolecules

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Tumor-associated macrophages (TAMs) have been detected in most skin cancers. TAMs produce various chemokines and angiogenic factors that promote tumor development, along with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils. TAMs generated from monocytes develop into functional, fully activated macrophages, and TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment. Since TAMs express PD1 to maintain the immunosuppressive M2 phenotype by PD1/PD-L1 signaling from tumor cells, and the blockade of PD1/PD-L1 signaling by anti-PD1 antibodies (Abs) activate and re-polarize TAMs into immunoreactive M1 phenotypes, TAMs represent a potential target for anti-PD1 Abs. The main population of TAMs comprises CD163+ M2 macrophages, and CD163+ TAMs release soluble (s)CD163 and several proinflammatory chemokines (CXCL5, CXCL10, CCL19, etc.) as a result of TAM activation to induce an immunosuppressive tumor microenvironment together with other immunosuppressive cells. Since direct blockade of PD1/PD-L1 signaling between tumor cells and tumor-infiltrating T cells (both effector T cells and Tregs) is mandatory for inducing an anti-immune response by anti-PD1 Abs, anti-PD1 Abs need to reach the tumor microenvironment to induce anti-immune responses in the tumor-bearing host. Taken together, TAM-related factors could offer a biomarker for anti-PD1 Ab-based immunotherapy. Understanding the crosstalk between TAMs and immunosuppressive cells is important for optimizing PD1 Ab-based immunotherapy.

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The Generation and Identity of Human Myeloid-Derived Suppressor Cells

Cited by 81 publications

References 114 publications

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

Human MDSCs derived from the bone marrow maintain their functional ability but have a reduced frequency of induction in the elderly compared to pediatric donors

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

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