Myeloid-Derived Suppressor Cells as Therapeutic Targets in Uterine Cervical and Endometrial Cancers

Mabuchi, Seiji; Sasano, Tomoyuki

doi:10.3390/cells10051073

Cited by 9 publications

(10 citation statements)

References 77 publications

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“…One study [ 164 ] conveyed that elevated MDSCs in gastrointestinal cancers could serve as an independent prognostic factor for decreased survival, normally linked with an elevation of IL-13, arginase-1, and Tregs. Similar findings are also described in gynecological cancers [ 165 , 166 ]. Shimura et al [ 167 ] indicated that immune suppression mediated by G-CSF-induced MDSCs could be the reason leading to the poor prognosis in gynecological cancer patients.…”

Section: Mdscs In Patients With Solid Tumorssupporting

confidence: 88%

Myeloid-Derived Suppressor Cells in Solid Tumors

Renz

Ilmer

et al. 2022

Cells

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Myeloid-derived suppressor cells (MDSCs) are one of the main suppressive cell population of the immune system. They play a pivotal role in the establishment of the tumor microenvironment (TME). In the context of cancers or other pathological conditions, MDSCs can differentiate, expand, and migrate in large quantities during circulation, inhibiting the cytotoxic functions of T cells and NK cells. This process is regulated by ROS, iNOS/NO, arginase-1, and multiple soluble cytokines. The definition of MDSCs and their phenotypes in humans are not as well represented as in other organisms such as mice, owing to the absence of the cognate molecule. However, a comprehensive understanding of the differences between different species and subsets will be beneficial for clarifying the immunosuppressive properties and potential clinical values of these cells during tumor progression. Recently, experimental evidence and clinical investigations have demonstrated that MDSCs have a close relationship with poor prognosis and drug resistance, which is considered to be a leading marker for practical applications and therapeutic methods. In this review, we summarize the remarkable position of MDSCs in solid tumors, explain their classifications in different models, and introduce new treatment approaches to target MDSCs to better understand the advancement of new approaches to cancer treatment.

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Section: Mdscs In Patients With Solid Tumorssupporting

confidence: 88%

Myeloid-Derived Suppressor Cells in Solid Tumors

Renz

Ilmer

et al. 2022

Cells

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“…MDSCs are immature myeloid cells with immune suppressive action based on L-arginine depletion in the tumor microenvironment, causing T-cell receptor downregulation [36]. MDSC levels are higher in EC than in normal endometrium [30], increase with advanced stage disease, and are associated with poor prognosis and poor response to cytotoxic treatments [37]. Tumor-associated macrophages (TAMs) are also involved in EC immune escape.…”

Section: Other Immune-response Related Features In Endometrial Cancermentioning

confidence: 99%

Endometrial Carcinoma: Immune Microenvironment and Emerging Treatments in Immuno-Oncology

et al. 2021

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Endometrial cancer (EC) can easily be cured when diagnosed at an early stage. However, advanced and metastatic EC is a common disease, affecting more than 15,000 patients per year in the United Sates. Only limited treatment options were available until recently, with a taxane–platinum combination as the gold standard in first-line setting and no efficient second-line chemotherapy or hormone therapy. EC can be split into four molecular subtypes, including hypermutated cases with POLE mutations and 25–30% harboring a microsatellite instability (MSI) phenotype with mismatch repair deficiency (dMMR). These tumors display a high load of frameshift mutations, leading to increased expression of neoantigens that can be targeted by the immune system, including (but not limited) to T-cell response. Recent data have demonstrated this impact of programmed death 1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors on chemo-resistant metastatic EC. The uncontrolled KEYNOTE-158 and GARNET trials have shown high response rates with pembrolizumab and dostarlimab in chemoresistant MSI-high tumors. Most responders experiment long responses that last more than one year. Similar, encouraging results were obtained for MMR proficient (MMRp) cases treated with a combination of pembrolizumab and the angiogenesis inhibitor lenvatinib. Approvals have, thus, been obtained or are underway for EC with immune checkpoint inhibitors (ICI) used as monotherapy, and in combination with antiangiogenic agents. Combinations with other targeted therapies are under evaluation and randomized studies are ongoing to explore the impact of ICI-chemotherapy triplets in first-line setting. We summarize in this review the current knowledge of the immune environment of EC, both for MMRd and MMRp tumors. We also detail the main clinical data regarding PD-1/PD-L1 inhibitors and discuss the next steps of development for immunotherapy, including various ICI-based combinations planned to limit resistance to immunotherapy.

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“…Similar to “premetastatic niche” models of distant sites, according to which the primary tumor “prepares” a potential metastatic site to “better accommodate” future metastatic cells, the premetastatic lymph node niche (PLNN) model has also been suggested. The interest in characterizing a possible premetastatic lymph node niche lies in characterizing the metastatic potential of a certain tumor, since a premetastatic niche favoring the dissemination of tumor cells would constitute the first key step in the metastatic cascade, and, thus, identify the best potential molecular targets [ 4 , 5 , 6 ]. The PLNN is characterized, according to preclinical models, by the development of an immunosuppressive immune microenvironment, especially driven by myeloid-derived suppressor cells (MDSCs), which are currently promising therapeutic targets [ 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…The interest in characterizing a possible premetastatic lymph node niche lies in characterizing the metastatic potential of a certain tumor, since a premetastatic niche favoring the dissemination of tumor cells would constitute the first key step in the metastatic cascade, and, thus, identify the best potential molecular targets [ 4 , 5 , 6 ]. The PLNN is characterized, according to preclinical models, by the development of an immunosuppressive immune microenvironment, especially driven by myeloid-derived suppressor cells (MDSCs), which are currently promising therapeutic targets [ 4 , 5 , 6 ]. MDSCs are produced after stimulation by molecules or vesicles (exosomes) secreted by tumor cells, and they act as T-cell suppressors [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…The PLNN is characterized, according to preclinical models, by the development of an immunosuppressive immune microenvironment, especially driven by myeloid-derived suppressor cells (MDSCs), which are currently promising therapeutic targets [ 4 , 5 , 6 ]. MDSCs are produced after stimulation by molecules or vesicles (exosomes) secreted by tumor cells, and they act as T-cell suppressors [ 6 ]. In addition to this immunosuppression, other factors, such as the extracellular matrix [ 7 ], are also modified in a context of the “preparation” of the tissue to receive a metastasis.…”

Section: Introductionmentioning

confidence: 99%

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The Premetastatic Lymph Node Niche in Gynecologic Cancer

Karpathiou

Orlando

Dumollard

et al. 2023

IJMS

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It has been suggested that a primary tumor can “prepare” the draining of lymph nodes to “better accommodate” future metastatic cells, thus implying the presence of a premetastatic lymph node niche. However, this phenomenon remains unclear in gynecological cancers. The aim of this study was to evaluate lymph-node draining in gynecological cancers for premetastatic niche factors, such as myeloid-derived suppressor cells (MDSCs), immunosuppressive macrophages, cytotoxic T cells, immuno-modulatory molecules, and factors of the extracellular matrix. This is a monocentric retrospective study of patients who underwent lymph-node excision during their gynecological-cancer treatment. In all, 63 non-metastatic pelvic or inguinal lymph nodes, 25 non-metastatic para-aortic lymph nodes, 13 metastatic lymph nodes, and 21 non-cancer-associated lymph nodes (normal controls) were compared for the immunohistochemical presence of CD8 cytotoxic T cells, CD163 M2 macrophages, S100A8/A9 MDSCs, PD-L1+ immune cells, and tenascin-C, which is a matrix remodeling factor. PD-L1-positive immune cells were significantly higher in the control group, in comparison to the regional and distant cancer-draining lymph nodes. Tenascin-C was higher in metastatic lymph nodes than in both non-metastatic nodes and control lymph nodes. Vulvar cancer-draining lymph nodes showed higher PD-L1 values than endometrial cancer and cervical cancer-draining lymph nodes. Endometrial cancer-draining nodes had higher CD163 values and lower CD8 values, compared to vulvar cancer-draining nodes. Regarding regional draining nodes in low- and high-grade endometrial tumors, the former showed lower S100A8/A9 and CD163 values. Gynecological cancer-draining lymph nodes are generally immunocompetent, but vulvar cancer draining nodes, as well as high-grade endometrial cancer draining nodes, are more susceptible to harboring premetastatic niche factors.

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Myeloid-Derived Suppressor Cells as Therapeutic Targets in Uterine Cervical and Endometrial Cancers

Cited by 9 publications

References 77 publications

Myeloid-Derived Suppressor Cells in Solid Tumors

Myeloid-Derived Suppressor Cells in Solid Tumors

Endometrial Carcinoma: Immune Microenvironment and Emerging Treatments in Immuno-Oncology

The Premetastatic Lymph Node Niche in Gynecologic Cancer

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