scholarly journals Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer

2020 ◽  
Vol 3 (11) ◽  
pp. e202000893
Author(s):  
Meliha Mehmeti-Ajradini ◽  
Caroline Bergenfelz ◽  
Anna-Maria Larsson ◽  
Robert Carlsson ◽  
Kristian Riesbeck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Immune Cell ◽  
Human Tumor ◽  
Metastatic Breast ◽  
Suppressor Cells ◽  
Breast Cancer Patients ◽  
Maturation Stages

Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.

scholarly journals cPLA2 Blockade Attenuates S100A7-Mediated Breast Tumorigenicity by Inhibiting the Immunosuppressive Tumor Microenvironment

2021 ◽  
Author(s):  
SANJAY MISHRA ◽  
Manish Charan ◽  
Rajni Kant Shukla ◽  
Pranay Agarwal ◽  
Swati Misri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Immunosuppressive Tumor Microenvironment ◽  
Tumor Growth And Metastasis ◽  
Breast Cancer Growth

Abstract Background: Metastasis is the major cause of mortality in breast cancer; however, the molecular mechanisms remain elusive. In our previous study, we demonstrated that S100A7/RAGE mediates breast cancer growth and metastasis by recruitment of tumor-associated macrophages. However, the downstream S100A7-mediated inflammatory oncogenic signaling cascade that enhances breast tumor growth and metastasis by generating the immunosuppressive tumor microenvironment (iTME) has not been studied. In this present study, we aimed to investigate the S100A7 and cPLA2 cross-talk in enhancing tumor growth and metastasis through enhancing the iTME.Methods: Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2 titer. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3(1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effect of S100A7/cPLA2 inhibition on the recruitment of various immune cells.Results: S100A7 and cPLA2 are highly expressed and positively correlated in malignant breast cancer patients. S100A7/RAGE upregulates cPLA2/PGE2 axis in aggressive breast cancer cells. Furthermore, S100A7 is positively correlated with PGE2 in breast cancer patients. Moreover, cPLA2 pharmacological inhibition suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models. Mechanistically, S100A7-mediated activation of cPLA2 enhances the recruitment of immunosuppressive myeloid cells by increasing PGE2 to fuel breast cancer growth and its secondary spread. We revealed that cPLA2 inhibitor mitigates S100A7-mediated breast tumorigenicity by suppressing the iTME. Furthermore, CODEX imaging data showed that cPLA2 inhibition increased the infiltration of CD4+/CD8+ T cells in the TME. Analysis of metastatic breast cancer samples revealed a positive correlation between S100A7/cPLA2 with CD163+ tumor-associated M2-macrophages.Conclusions: Our study shows that cross-talk between S100A7 and cPLA2 plays an important role in enhancing breast tumor growth and metastasis by generating an immunosuppressive tumor microenvironment and reducing infiltration of T cells. Furthermore, S100A7 could be used as a novel non-invasive prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing metastatic breast cancer.

Effects of melatonin and doxorubicin on primary tumor and metastasis in breast cancer model

2021 ◽  
Vol 21 ◽  
Author(s):  
Gamze Tanriover ◽  
Sayra Dilmac ◽  
Gunes Aytac ◽  
Ammad Ahmad Farooqi ◽  
Muzaffer Sindel
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Patients ◽  
Primary Tumor ◽  
Metastatic Breast ◽  
Suppressor Cells ◽  
Metastatic Tumor ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Ample Evidence

Background: Melatonin exerts oncostatic effects on breast cancer via immunomodulation and anti-oxidation. Doxorubicin is an effective chemotherapeutic agent, but parallel studies also provide ample evidence of an off-target effect of Doxorubicin in breast cancer patients. Objective: Combinatorial use of doxorubicin and melatonin has not been comprehensively analyzed in breast cancer models. We hypothesized that the anti-oxidative, anti-proliferative and anti-inflammatory effects of melatonin could ameliorate the off-target effects of doxorubicin in breast cancer patients and enhance the anti-tumoral effects of doxorubicin. The goal of the study is to test this hypothesis in cancer cell lines and xenografted mice. Methods: The effects of Melatonin and doxorubicin on the cell viability were evaluated in 4T1-Brain Metastatic Tumor (4TBM). Furthermore, the effects of melatonin and doxorubicin on the primary tumors and systemic metastasis were evaluated in the xenografted mice. Lung and liver tissues were removed and metastasis analyses were performed. The levels of p65, phospho-STAT3, CD11b+, GR1+, Ki67, and cleaved caspase-3 proteins were determined with immunohistochemistry and western blot analysis. We examined the effects of melatonin and Melatonin+Doxorubicin combination therapy on 4TBM cells. Results: Our results showed that doxorubicin inhibited the proliferation of metastatic breast cancer cells while melatonin did not affect cells. Tumor growth and metastasis were markedly suppressed in melatonin alone and combination with doxorubicin. The expression of CD11b+ and GR1+ proteins which are indicators of myeloid-derived suppressor cells (MDSCs) were noted to be reduced in both primary tumor and metastatic tissues in melatonin and doxorubicin groups. Conclusion: The combination of melatonin with doxorubicin reduced primary tumor growth and distant metastasis. Based on these results, melatonin is a promising candidate for combinatory use with conventional chemotherapeutics for breast cancer treatment.

Abstract PS17-37: Immune cell populations in peripheral blood of metastatic breast cancer patients under CDK4/6 inhibitors

2021 ◽  
Author(s):  
Soraia Lobo-Martins ◽  
Patrícia Corredeira ◽  
Patrícia Borges Alves ◽  
Marília Antunes ◽  
Ângela Rodrigues ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Metastatic Breast ◽  
Cell Populations ◽  
Breast Cancer Patients

scholarly journals Impact of Physical Activity on Oxidative Stress Markers in Patients with Metastatic Breast Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Lidia Delrieu ◽  
Marina Touillaud ◽  
Olivia Pérol ◽  
Magali Morelle ◽  
Agnès Martin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Physical Activity ◽  
Enzyme Activity ◽  
Metastatic Breast Cancer ◽  
Tumor Progression ◽  
Plasma Concentrations ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Oxidative Stress Biomarkers

Purpose. Regular physical activity (PA) can affect oxidative stress, known to be involved in carcinogenesis. The objective of this study was to evaluate the associations between a six-month PA intervention and oxidative stress biomarkers, PA, and clinical outcomes in patients with metastatic breast cancer. Methods. Forty-nine newly diagnosed patients with metastatic breast cancer were recruited for a single-arm, unsupervised, and personalized six-month walking intervention with activity tracker. PA level and PA fitness, plasma concentrations of DNA oxidation (8OhdG), lipid peroxidation (MDA), and protein oxidation (AOPP), plasma activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase, plasma and leucocyte activities of myeloperoxidase (MPO) and NADPH oxidase (NOX), and clinical markers of tumor progression (RECIST criteria) were measured at baseline and after the six-month intervention. Results. GPX activity (+17%) and MDA (+9%) significantly increased between baseline and the end of the intervention. Changes in PA level and fitness were significantly positively correlated with changes in plasma GPX and significantly negatively with changes in NOX in the leucocytes. Plasma MDA was significantly higher (+20%) whereas plasma AOPP was lower (-46%) for patients with tumor progression or that died during the six months as compared to patients without progression. Conclusion. A six-month PA intervention may be potentially beneficial in metastatic breast cancer patients for enhancing antioxidant enzyme activity and decreasing prooxidant enzyme activity. Moreover, AOPP and MDA could also be favorable and unfavorable biomarkers, respectively, since they are associated with disease progression and fitness level in this population. This trial is registered with NCT number: NCT03148886.

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