scholarly journals Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells

2021 ◽  
Vol 22 (10) ◽  
pp. 5150
Author(s):  
Nehal Gupta ◽  
Shreyas Gaikwad ◽  
Itishree Kaushik ◽  
Stephen E. Wright ◽  
Maciej M. Markiewski ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Progression ◽  
Breast Tumor ◽  
Triple Negative ◽  
Immune Surveillance ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
In Vivo Models ◽  
Ribosomal Protein S19

A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cytokines TGF-β and IL-10 and induce regulatory T cells (Tregs), all of which are immunosuppressive and enhance tumor progression. Hence, enhancing the immune system in breast tumors could be a strategy for anticancer therapeutics. The present study evaluated the immune response of atovaquone, an antiprotozoal drug, in three independent breast-tumor models. Our results demonstrated that oral administration of atovaquone reduced HCC1806, CI66 and 4T1 paclitaxel-resistant (4T1-PR) breast-tumor growth by 45%, 70% and 42%, respectively. MDSCs, TGF-β, IL-10 and Tregs of blood and tumors were analyzed from all of these in vivo models. Our results demonstrated that atovaquone treatment in mice bearing HCC1806 tumors reduced MDSCs from tumor and blood by 70% and 30%, respectively. We also observed a 25% reduction in tumor MDSCs in atovaquone-treated mice bearing CI66 and 4T1-PR tumors. In addition, a decrease in TGF-β and IL-10 in tumor lysates was observed in atovaquone-treated mice with a reduction in tumor Tregs. Moreover, a significant reduction in the expression of RPS19 was found in tumors treated with atovaquone.

Reduction-responsive core-crosslinked hyaluronic acid-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate) micelles: synthesis and CD44-mediated potent delivery of docetaxel to triple negative breast tumor in vivo

2018 ◽  
Vol 6 (19) ◽  
pp. 3040-3047 ◽  
Author(s):  
Yaqin Zhu ◽  
Jian Zhang ◽  
Fenghua Meng ◽  
Liang Cheng ◽  
Jan Feijen ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Tumor Growth ◽  
Breast Tumor ◽  
Triple Negative ◽  
Trimethylene Carbonate ◽  
Inhibit Tumor Growth

Docetaxel-loaded core crosslinked HA-P(TMC-DTC) micelles show high targetability to CD44-overexpressing MDA-MB-231 breast tumor and effectively inhibit tumor growth.

scholarly journals IMMU-28. TARGETING IMMUNOSUPPRESSIVE MYELOID DERIVED SUPPRESSOR CELLS VIA MIF/CD74 SIGNALING AXIS TO ATTENUATE GBM GROWTH

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi125-vi125
Author(s):  
Tyler Alban ◽  
Defne Bayik ◽  
Balint Otvos ◽  
Matthew Grabowski ◽  
Manmeet Ahluwalia ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Immune Cell ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Signaling Axis ◽  
Immunosuppressive Microenvironment ◽  
And Function

Abstract The immunosuppressive microenvironment in glioblastoma (GBM) enables persistent tumor growth and evasion from tumoricidal immune cell recognition. Despite a large accumulation of immune cells in the GBM microenvironment, tumor growth continues, and evidence for potent immunosuppression via myeloid derived suppressor cells (MDSCs) is now emerging. In agreement with these observations, we have recently established that increased MDSCs over time correlates with poor prognosis in GBM, making these cells of interest for therapeutic targeting. In seeking to reduce MDSCs in GBM, we previously identified the cytokine macrophage migration inhibitory factor (MIF) as a possible activator of MDSC function in GBM. Here, using a novel in vitro co-culture system to reproducibly and rapidly create GBM-educated MDSCs, we observed that MIF was essential in the generation of MDSCs and that MDSCs generated via this approach express a repertoire of MIF receptors. CD74 was the primary MIF receptor in monocytic MDSCs (M-MDSC), which penetrate the tumor microenvironment in preclinical models and patient samples. A screen of MIF/CD74 interaction inhibitors revealed that MN-166, a clinically relevant blood brain barrier penetrant drug, which is currently fast tracked for FDA approval, reduced MDSC generation and function in vitro. This effect was specific to M-MDSC subsets expressing CD74, and appeared as reduced downstream pERK signaling and MCP-1 secretion. In vivo, MN-166 was able reduce tumor-infiltrating MDSCs, while conferring a significant increase in survival in the syngeneic glioma model GL261. These data provide proof of concept that M-MDSCs can be targeted in the tumor microenvironment via MN-166 to reduce tumor growth and provide a rationale for future clinical assessment of MN-166 to reduce M-MDSCs in the tumor microenvironment. Ongoing studies are assessing the effects of MDSC inhibition in combination with immune activating approaches, in order to inhibit immune suppression while simultaneously activating the immune system.

Myeloid-derived suppressor cells as a potential treatment target for pancreas adenocarcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 194-194
Author(s):  
M. R. Porembka ◽  
J. B. Mitchem ◽  
P. S. Goedegebuure ◽  
D. Linehan
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Animal Studies ◽  
Suppressor Cells ◽  
Disease Stage ◽  
Tumor Growth Rate ◽  
Myeloid Derived Suppressor Cells ◽  
Pancreas Adenocarcinoma

194 Background: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA). Here, we quantify MDSC prevalence in patients with PA and assess the efficacy of MDSC depletion in a murine model of PA. Methods: Peripheral blood and tumor samples were collected from patients with PA, analyzed for MDSC (CD15+11b+) by flow cytometry (FC) and compared to cancer-free controls (CFC). The suppressive capacity of MDSC and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid (ZA), a potent aminobisphosphonate previously shown to target MDSC. Endpoints included tumor size, survival, and MDSC prevalence. Tumor cell infiltrate was analyzed by FC for MDSC (Gr1+CD11b+) and effector T cells; tumor cytokine levels were measured by Luminex assay. Results: Patients with PA demonstrated increased circulating MDSC compared to CFC, which correlated with disease stage (metastatic PA: 68%±3.6% of CD45+ cells, resectable PA: 57%±3.5%, CFC: 37%±3.6%; p<0.0001). Normal pancreas tissue showed no MDSC infiltrate while PA avidly recruited CD11b+15+ cells to the primary tumor. Murine tumors similarly recruited MDSC that actively suppressed CD8+ T cells in vitro measured by CFSE dilution and accelerated tumor growth in vivo by adoptive transfer with Pan02 cells (p<0.001). Treatment with ZA impaired MDSC accumulation in the tumor (Placebo: 78%, ZA: 51%, p<0.05) resulting in delayed tumor growth rate (p<0.0001) and prolonged median survival (Placebo: 59 days, ZA: 73 days, p<0.05). MDSC blockade increased recruitment of T cells to the tumor (CD4: 4.4%±1.1% vs 12.2%±2.0%, p<0.05; CD8: 3.9%±1.3% vs 10.6%±2.2%, p<0.05) and a more robust type 1 response with increased levels of IFN-g (p<0.05) and decreased levels of IL-10 (p<0.05). Conclusions: MDSC are an important mediator of tumor-induced immunosuppression in PA. Treatment with ZA effectively blocks MDSC accumulation improving anti-tumor response in animal studies. Efforts to block MDSC may represent a novel treatment strategy for PA. [Table: see text]

Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice

Blood ◽  
2008 ◽  
Vol 111 (12) ◽  
pp. 5457-5466 ◽  
Author(s):  
Yasushi Sawanobori ◽  
Satoshi Ueha ◽  
Makoto Kurachi ◽  
Takeshi Shimaoka ◽  
James E. Talmadge ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Development ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Bearing ◽  
Promote Tumor Growth ◽  
Brdu Labeling ◽  
And Migration ◽  
Stimulating Factor

Abstract Tumor growth is associated with aberrant myelopoiesis, including the accumulation of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) that have the potential to promote tumor growth. However, the identity, growth, and migration of tumor-associated MDSCs remain undefined. We demonstrate herein that MDSCs at tumor site were composed primarily of bone marrow-derived CD11b+Gr-1hiLy-6Cint neutrophils and CD11b+Gr-1int/dullLy-6Chi macrophages. Unexpectedly, in vivo bromodeoxyuridine (BrdU) labeling and parabiosis experiments revealed that tumor-infiltrating macrophages were replenished more rapidly than neutrophils. CCR2 deficiency caused striking conversion of infiltrating cellular dominance from macrophages to neutrophils in the tumor with the excessive production of CXCR2 ligands and granulocyte-colony stimulating factor in the tumor without affecting tumor growth. Overall, our data established the identity and dynamics of MDSCs in a tumor-bearing host mediated by chemokines and elucidated unexpected effects of the paucity of macrophages on tumor development.

scholarly journals Anti-GD2 antibody dinutuximab inhibits triple-negative breast tumor growth by targeting GD2+ breast cancer stem-like cells

2021 ◽  
Vol 9 (3) ◽  
pp. e001197
Author(s):  
Stanley Ly ◽  
Vivek Anand ◽  
Fouad El-Dana ◽  
Khoa Nguyen ◽  
Yiming Cai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Tumor Growth ◽  
Cell Line ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
In Vivo Models ◽  
Tnbc Cell ◽  
Tnbc Cell Line

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no effective standard therapy. Breast cancer stem-like cells (BCSCs) in primary TNBCs are reported to be responsible for metastatic spread of the disease and resistance to chemotherapy, but no available therapeutic tools target BCSCs. We previously reported that the ganglioside GD2 is highly expressed on BCSCs and that inhibition of its expression hampers TNBC growth. We therefore hypothesized that the anti-GD2 antibody dinutuximab (ch14.18) targets GD2+ BCSCs and inhibits TNBC growth.MethodTo test our hypothesis, we first determined GD2 expression via immunohistochemistry in frozen primary tumor samples from patients with TNBC (n=89). Then, we examined the effects of dinutuximab on TNBC cell adhesion, migration, and mammosphere formation in vitro and on tumor growth in vivo using TNBC cell-line and patient-derived xenograft (PDX) models.ResultsWe found that GD2 was expressed in around 60% of primary TNBC tumors at variable levels and was associated with worse overall survival of patients with TNBC (p=0.002). GD2 was found to be expressed in tumors and stroma, but normal ducts and lobules in adjacent tissues have shown low or no GD2 staining, indicating that GD2 is potentially a novel biomarker for tumor and its microenvironment. Treatment with dinutuximab significantly decreased adhesion and migration of MDA-MB-231 and SUM159 TNBC cells. Moreover, dinutuximab treatment inhibited mTOR signaling, which has been shown to be regulated by GD2 in BCSCs. Dinutuximab also reduced tumor growth in nude mice bearing TNBC cell-line xenografts. Finally, dinutuximab in combination with activated natural killer cells inhibited tumor growth in a TNBC PDX model and improved overall survival of tumor-bearing mice.ConclusionsDinutuximab successfully eliminated GD2+ cells and reduced tumor growth in both in vivo models. Our data provide proof-of-concept for the criticality of GD2 in BCSCs and demonstrate the potential of dinutuximab as a novel therapeutic approach for TNBC.

scholarly journals Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1170
Author(s):  
Mithunah Krishnamoorthy ◽  
Lara Gerhardt ◽  
Saman Maleki Maleki Vareki
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Cancer Progression ◽  
Suppressor Cells ◽  
T Cell Immunity ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Immunity ◽  
Promote Tumor Growth

The primary function of myeloid cells is to protect the host from infections. However, during cancer progression or states of chronic inflammation, these cells develop into myeloid-derived suppressor cells (MDSCs) that play a prominent role in suppressing anti-tumor immunity. Overcoming the suppressive effects of MDSCs is a major hurdle in cancer immunotherapy. Therefore, understanding the mechanisms by which MDSCs promote tumor growth is essential for improving current immunotherapies and developing new ones. This review explores mechanisms by which MDSCs suppress T-cell immunity and how this impacts the efficacy of commonly used immunotherapies.

scholarly journals Transforming Growth Factor-Beta1 and Myeloid-Derived Suppressor Cells Interplay in Cancer

2017 ◽  
Vol 6 (1) ◽  
pp. 1-14
Author(s):  
Juan F. Santibanez ◽  
Suncica Bjelica
Keyword(s):  
Immune System ◽  
Growth Factor ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Immune Surveillance ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

Background: Transforming growth factor-beta1 (TGF-β1) is a pleiotropic cytokine with a double role in cancer through its capacity to inhibit early stages of tumors while enhancing tumor progression at late stages of tumor progression. Moreover, TGF-β1 is a potent immunosuppressive cytokine within the tumor microenvironment that allows cancer cells to escape from immune surveillance, which largely contributes to the tumor progression. Method: It has been established that the cancer progression is commonly associated with increased number of Myeloid-derived suppressor cells (MDSC) that are a hallmark of cancer and a key mechanism of immune evasion. Result: MDSC represent a population of heterogeneous myeloid cells comprised of macrophages, granulocytes and dendritic cells at immature stages of development. MDSC promote tumor progression by regulating immune responses as well as tumor angiogenesis and cancer metastasis. Conclusion: In this review, we present an overview of the main key functions of both TGF-β1 and MDSC in cancer and in the immune system. Furthermore, the mutual contribution between TGF-β1 and MDSC in the regulation of immune system and cancer development will be analyzed.

532 SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of early-stage myeloid-derived suppressor cells via the miR-155/C/EBPß/Wnt axis

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A568-A568
Author(s):  
Jinpu Yu ◽  
Wenwen Zhang
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Rna Sequencing ◽  
Early Stage ◽  
Suppressor Cells ◽  
Myeloid Differentiation ◽  
Myeloid Derived Suppressor Cells ◽  
Mirna Microarray ◽  
Differentiation Block

BackgroundEarly-stage myeloid-derived suppressor cells (eMDSCs) are a newly defined subset of myeloid-derived suppressor cells (MDSCs) that accumulate densely in tumors and potently promote tumor growth and metastasis by suppressing antitumor immune responses in vitro and in vivo. We previously identified a subset of eMDSCs in human breast cancer with a characteristic phenotype of Lin-HLA-DR-CD33+. We also found that SOCS3 deficiency and sustained activation of the JAK/STAT signaling pathway are critical molecular events coordinating the differentiation of eMDSCs, although the distinct molecular regulation has not been fully elucidated.MethodsHerein, we genetically constructed conditional SOCS3 knockout mice with SOCS3 deficiency specifically in the myeloid linage (SOCS3MyeKO). We analyzed the number of eMDSCs in SOCS3MyeKO mice (eMDSCsSOCS3KO). To explore which pathways participated in dysfunctional eMDSC differentiation, we performed whole-genome RNA sequencing and miRNA microarray on CD11b+Gr-1+ cells, eMDSCsfl/fl and eMDSCsSOCS3KO to screen the potential regulatory ceRNA network in eMDSCsSOCS3KO. CD11b+Gr-1+ cells isolated from SOCS3fl/fl mouse spleens were used as mature myeloid cell controls. Furthermore, we applied a specific miR-155 antagonist and the autophagy agonist rapamycin to suppress tumor growth and eMDSC infiltration.ResultsThe transcriptome results and corresponding intervention experiment revealed that the differentiation block in eMDSCsSOCS3KO was caused by SOCS3 deficiency-mediated limited autophagy activation in an AMPK-independent manner. The results of miRNA microarray and RNA sequencing demonstrated that miR-155 overexpression and Wnt/ß-catenin pathway activation were involved in the SOCS3 knockout-mediated myeloid differentiation block and autophagy repression. Further experiments revealed that miR-155 was induced by activation of the STAT3/NK-?B pathway upon SOCS3 deficiency, which consequently activated the Wnt/ß-catenin pathway via targeting C/EBPß. Furthermore, applying a specific miR-155 antagonist or the autophagy agonist rapamycin efficiently suppressed tumor growth and eMDSC infiltration in vivo.ConclusionsOverall, these findings indicated that SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of e-MDSCs via the miR-155/C/EBPß/Wnt axis, and thus targeted therapy against this pathway could be a potential therapeutic target in breast cancer.

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