scholarly journals Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

2020 ◽  
Author(s):  
S. Mahnaz ◽  
L. Das Roy ◽  
M. Bose ◽  
C. De ◽  
S. Nath ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathways ◽  
Suppressor Cells ◽  
Ductal Adenocarcinoma ◽  
Myeloid Derived Suppressor Cells ◽  
Mucin 1 ◽  
Transmembrane Glycoprotein ◽  
The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

scholarly journals Repression of MUC1 Promotes Expansion and Suppressive Function of Myeloid-Derived Suppressor Cells in Pancreatic and Breast Cancer Murine Models

2021 ◽  
Vol 22 (11) ◽  
pp. 5587
Author(s):  
Mahnaz Sahraei ◽  
Mukulika Bose ◽  
J. Alexa Sanders ◽  
Chandrav De ◽  
Lopamudra DasRoy ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cell Function ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Mucin 1 ◽  
Transmembrane Glycoprotein ◽  
Suppressive Phenotype ◽  
The Impact

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing syngeneic pancreatic (KCKO) or breast (C57MG) tumors. We observed enhanced tumor growth of pancreatic and breast tumors in the MUC1KO mice compared to the WT mice. Enhanced tumor growth in the MUC1KO mice was associated with increased numbers of suppressive MDSCs and T regulatory (Tregs) cells in the tumor microenvironment. Compared to the WT host, MUC1KO host showed higher levels of iNOS, ARG1, and TGF-β, thus promoting proliferation of MDSCs with an immature and immune suppressive phenotype. When co-cultured with effector T cells, MDSCs from MUC1KO mice led to higher repression of IL-2 and IFN-γ production by T cells as compared to MDSCs from WT mice. Lastly, MDSCs from MUC1KO mice showed higher levels of c-Myc and activated pSTAT3 as compared to MDSCs from WT mice, suggesting increased survival, proliferation, and prevention of maturation of MDSCs in the MUC1KO host. We report diminished T cell function in the KO versus WT mice. In summary, the data suggest that MUC1 may regulate signaling pathways that are critical to maintain the immunosuppressive properties of MDSCs.

scholarly journals Arginine and Arginases Modulate Metabolism, Tumor Microenvironment and Prostate Cancer Progression

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4503
Author(s):  
Andreia Matos ◽  
Marcos Carvalho ◽  
Manuel Bicho ◽  
Ricardo Ribeiro
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Urea Cycle ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Prostate Cancer Progression ◽  
Arginine Metabolism ◽  
Arginine Deprivation ◽  
The Impact

Arginine availability and activation of arginine-related pathways at cancer sites have profound effects on the tumor microenvironment, far beyond their well-known role in the hepatic urea cycle. Arginine metabolism impacts not only malignant cells but also the surrounding immune cells behavior, modulating growth, survival, and immunosurveillance mechanisms, either through an arginase-mediated effect on polyamines and proline synthesis, or by the arginine/nitric oxide pathway in tumor cells, antitumor T-cells, myeloid-derived suppressor cells, and macrophages. This review presents evidence concerning the impact of arginine metabolism and arginase activity in the prostate cancer microenvironment, highlighting the recent advances in immunotherapy, which might be relevant for prostate cancer. Even though further research is required, arginine deprivation may represent a novel antimetabolite strategy for the treatment of arginine-dependent prostate cancer.

scholarly journals Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma

2019 ◽  
Vol 216 (3) ◽  
pp. 656-673 ◽  
Author(s):  
Jing Liu ◽  
Wenna Jiang ◽  
Kaili Zhao ◽  
Hongwei Wang ◽  
Tianxing Zhou ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cd8 T Cells ◽  
Response Rate ◽  
Suppressor Cells ◽  
Ductal Adenocarcinoma ◽  
Myeloid Derived Suppressor Cells ◽  
Immune Microenvironment ◽  
Gm Csf ◽  
Ets Homologous Factor ◽  
Efficacy Prediction

Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion of T reg cells and MDSCs through inhibiting tumor TGFβ1 and GM-CSF secretion. EHF suppressed the transcription of TGFB1 and CSF2 by directly binding to their promoters. Mice bearing EHF overexpression tumors exhibited significantly better response to anti-PD1 therapy than those with control tumors. Our findings delineate the immunosuppressive mechanism of EHF deficiency in PDAC and highlight that EHF overexpression may improve PDAC checkpoint immunotherapy.

scholarly journals The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 210
Author(s):  
Maximilian Haist ◽  
Henner Stege ◽  
Stephan Grabbe ◽  
Matthias Bros
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Metastatic Cancer ◽  
Suppressor Cells ◽  
Cell Populations ◽  
Myeloid Derived Suppressor Cells ◽  
Immunosuppressive Cell ◽  
The Impact

Immune checkpoint inhibitors (ICI) have led to profound and durable tumor regression in some patients with metastatic cancer diseases. However, many patients still do not derive benefit from immunotherapy. Here, the accumulation of immunosuppressive cell populations within the tumor microenvironment (TME), such as myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and regulatory T cells (Treg), contributes to the development of immune resistance. MDSC and Treg expand systematically in tumor patients and inhibit T cell activation and T effector cell function. Numerous studies have shown that the immunosuppressive mechanisms exerted by those inhibitory cell populations comprise soluble immunomodulatory mediators and receptor interactions. The latter are also required for the crosstalk of MDSC and Treg, raising questions about the relevance of cell–cell contacts for the establishment of their inhibitory properties. This review aims to outline the current knowledge on the crosstalk between these two cell populations, issuing particularly the potential role of cell adhesion molecules. In this regard, we further discuss the relevance of β2 integrins, which are essential for the differentiation and function of leukocytes as well as for MDSC–Treg interaction. Lastly, we aim to describe the impact of such bidirectional crosstalk for basic and applied cancer research and discuss how the targeting of these pathways might pave the way for future approaches in immunotherapy.

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