The blockage of Notch signalling promoted the generation of polymorphonuclear myeloid-derived suppressor cells with lower immunosuppression

Wang, Shuhong; Lu, Qingyang; Guo, Ya-Huan; Liu, Peijun; Wang, Yao-Chun

doi:10.1016/j.ejca.2016.08.019

Cited by 34 publications

(31 citation statements)

References 34 publications

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“…Indeed, recent studies have shown that Notch signaling can regulate MDSC differentiation. Blockage of Notch signaling promoted the differentiation and expansion of G-MDSCs both in vitro and in vivo (29,56). Our finding of a reduction in G-MDSCs upon Notch activation, although not statistically significant, would be consistent with this effect ( Fig.…”

Section: Discussionsupporting

confidence: 80%

Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting

et al. 2018

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Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multilayered tumor microenvironment. In this study, we employed a dual recombinase-based strategy to modulate Notch signaling specifically in myeloid cells to dissect the tumorigenic role of Notch in PDAC stroma. Pancreas-specific KrasG12D activation and loss of Tp53 was induced using a Pdx1-Flp transgene, whereas Notch signaling was genetically targeted using a myeloid-targeting Lyz2-Cre strain for either activation of Notch2-IC or deletion of Rbpj. Myeloid-specific Notch activation significantly decreased tumor infiltration by protumorigenic M2 macrophages in spontaneous endogenous PDAC, which translated into significant survival benefit. Further characterization revealed upregulated antigen presentation and cytotoxic T effector phenotype upon Notch-induced M2 reduction. This approach is the first proof of concept for genetic targeting and reprogramming of myeloid cells in a complex disease model of PDAC and provides evidence for a regulatory role of Notch signaling in intratumoral immune phenotypes. This study provides insight into the role of myeloid-dependent NOTCH signaling in PDAC and accentuates the need to dissect differential roles of signaling pathways in different cellular components within the tumor microenvironment. .

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Section: Discussionsupporting

confidence: 80%

Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting

et al. 2018

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“…This is caused by an inhibitory phosphorylation of the NICD by casein kinase 2, which disrupts the Notch transcriptional complex ( 66 ). In addition, inhibition of Notch promotes PMN-MDSCs over M-MDSCs and these cells had less immunosuppressive capacity when compared with the M-MDSCs when using a lower ratio of MDSCs to cancer cells ( 67 ). However, another study showed that deregulated Notch activity can cause myelopoiesis and expansion of MDSCs; this was caused by accumulation of a S2-cleaved Notch receptor, without S3 cleavage, through increased function of ADAM metalloproteases at the S2 site, or inhibition of γ-secretase (Figure 2 i) ( 68 ).…”

Section: Notch In the Cancer Immune Responsementioning

confidence: 99%

Notch Signaling as a Regulator of the Tumor Immune Response: To Target or Not To Target?

Janghorban

Rosen

et al. 2018

Front. Immunol.

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The Notch signaling pathway regulates important cellular processes involved in stem cell maintenance, proliferation, development, survival, and inflammation. These responses to Notch signaling involving both canonical and non-canonical pathways can be spatially and temporally variable and are highly cell-type dependent. Notch signaling can elicit opposite effects in regulating tumorigenicity (tumor-promoting versus tumor-suppressing function) as well as controlling immune cell responses. In various cancer types, Notch signaling elicits a “cancer stem cell (CSC)” phenotype that results in decreased proliferation, but resistance to various therapies, hence potentially contributing to cell dormancy and relapse. CSCs can reshape their niche by releasing paracrine factors and inflammatory cytokines, and the niche in return can support their quiescence and resistance to therapies as well as the immune response. Moreover, Notch signaling is one of the key regulators of hematopoiesis, immune cell differentiation, and inflammation and is implicated in various autoimmune diseases, carcinogenesis (leukemia), and tumor-induced immunosuppression. Notch can control the fate of various T cell types, including Th1, Th2, and the regulatory T cells (Tregs), and myeloid cells including macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs). Both MDSCs and Tregs play an important role in supporting tumor cells (and CSCs) and in evading the immune response. In this review, we will discuss how Notch signaling regulates multiple aspects of the tumor-promoting environment by elucidating its role in CSCs, hematopoiesis, normal immune cell differentiation, and subsequently in tumor-supporting immunogenicity.

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“…Interestingly, tumor-derived soluble factors, not yet identified, were responsible for the enhanced CKII activity [59]. Another group [60] confirmed that the Notch signaling is inhibited in MDSCs from tumor-bearing mice and that the modulation of the Notch pathway influenced destiny and suppressive functions of MDSCs. In fact, the treatment of mice with GSI inhibited the formation of M-MDSC, whereas it promoted that of PMN-MDSCs.…”

Section: Notch As An Emerging ''Modulator'' Of Mdscsmentioning

confidence: 94%

“…Moreover, RBP-Jk deficiency in MDSCs impairs both their ability to block dendritic cell-mediated activation of T cells in vitro and their function of improving tumor growth in vivo. The authors also produced evidence that the effects on MDSCs are achieved through a Notch/IL-6/STAT3 axis [60].…”

Section: Notch As An Emerging ''Modulator'' Of Mdscsmentioning

confidence: 99%

The mazy case of Notch and immunoregulatory cells

Grazioli

Felli

Screpanti

et al. 2017

Journal of Leukocyte Biology

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The Notch pathway represents a conserved signal transduction machinery that is straightforward and based on a few elements (ligands, receptors, transducers). However, the existence of multiple control levels of the Notch signaling final outcome makes it strictly context dependent and dose dependent. The function of Notch as a regulator of cell development and differentiation, as well as the aberrant consequences of its modulation, either positive or negative, is well established. In this review, we will discuss our current knowledge about Notch-dependent regulation of generation and function of 2 subsets of the immunoregulatory system, namely regulatory T cells (T) and myeloid-derived suppressor cells (MDSCs). Then, we will focus on an unforeseen mechanism that may unveil an additional way of Notch to govern the surrounding environment in cancer.

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The blockage of Notch signalling promoted the generation of polymorphonuclear myeloid-derived suppressor cells with lower immunosuppression

Cited by 34 publications

References 34 publications

Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting

Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting

Notch Signaling as a Regulator of the Tumor Immune Response: To Target or Not To Target?

The mazy case of Notch and immunoregulatory cells

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