Immature myeloid cells in the tumor microenvironment: Implications for immunotherapy

Kamran, Neha; Chandran, Mayuri; Löwenstein, Pedro R.; Castro, María G.

doi:10.1016/j.clim.2016.10.008

Cited by 42 publications

(37 citation statements)

References 123 publications

(193 reference statements)

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“…In the present paper, we aim at the revision of pharmacological strategies that interfere with GAMs' function, i.e., cell recruitment at the tumor site, cell inflammatory activation and immune function, and the extracellular matrix remodeling promoted by GAM-secreted factors. For recent advances on the biology of MDSCs and Tregs in the glioblastoma microenvironment and their potential role as therapeutic targets, we refer the readers to other review articles [20,21] .…”

Section: Introductionmentioning

confidence: 99%

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

Russo¹,

Cappoli²

2018

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Glioma associated microglia/macrophages (GAMs) constitute the largest proportion of glioma infiltrating cells, particularly in high grade tumors (i.e., glioblastoma). Once inside the tumors, GAMs usually acquire a specific phenotype of activation that favors tumor growth, angiogenesis and promotes the invasion of normal brain parenchyma. Therefore, treatments that limit or prevent GAMs' recruitment at the tumor site or modulate their immune activation promoting antitumor activities are expected to exert beneficial effects in glioblastoma. In the present paper, we aim at the revision of pharmacological strategies that interfere with GAMs' function and are currently proposed as an alternative/additional option to current approved cytotoxic regimens.

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Section: Introductionmentioning

confidence: 99%

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

Russo¹,

Cappoli²

2018

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“…3e). These tumours are known to be highly infiltrated with myeloid cells, which may serve as an additional immunosuppressive mechanism preventing efficacy with ICI therapy 36,37 . Notably, these cancer types were also characterized by elevated IMS scores (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ratio of the interferon-γsignature to the immunosuppression signature predicts anti-PD-1 therapy response in melanoma

Kong

Cui

et al. 2020

Preprint

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Immune checkpoint inhibitor (ICI) treatments produce clinical benefit in many patients. However, better pretreatment predictive biomarkers for ICI are still needed to help match individual patients to the treatment most likely to be of benefit. Existing gene expression profiling (GEP)-based biomarkers for ICI are primarily focused on measuring a T cell-inflamed tumour microenvironment that contributes positively to the response to ICI. Here, we identified an immunosuppression signature (IMS) through analysing RNA sequencing data from a combined discovery cohort (n = 120) consisting of three publicly available melanoma datasets. Using the ratio of an established IFN-γ signature and IMS led to consistently better prediction of the ICI therapy outcome compared to a collection of nine published GEP signatures from the literature on a newly generated internal validation cohort (n = 55) and three published datasets of metastatic melanoma treated with anti-PD-1 (n = 48) and anti-CTLA-4 (n = 42) as well as in patients with gastric cancer treated with anti-PD-1 (n = 45), demonstrating the potential utility of IMS as a predictive/prognostic biomarker that complements existing GEP signatures for immunotherapy.

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“…We and others have previously reported that glioma infiltrating MDSCs play a key role in inhibiting anti-tumor T-cell immune responses, thus promoting tumor progression 18 . The inhibitory immune-microenvironment in glioma is thought to contribute to the ineffectiveness of immunotherapies 31 . Novel therapeutics approaches that reverse the inhibitory microenvironment are essential to counteract these effects, and we propose that the inhibition of FYN within glioma cells could represent such a strategy.…”

Section: Discussionmentioning

confidence: 99%

FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses

Comba

Dunn

Argento

et al. 2019

Preprint

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BackgroundHigh grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas. FYN’s role in vivo in glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion.MethodsWe evaluated the role of FYN using genetically engineered mouse glioma models (GEMM). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (NSG, CD8−/−, CD4−/−). We analyzed molecular mechanism by RNA-Seq and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME.ResultsWe demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontologies (GOs) analysis of differentially expressed genes in wild type vs. FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG, CD8−/− and CD4−/− immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces anti-glioma immune activation. Examination of glioma immune infiltrates by flow-cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells (MDSCs) in the FYN glioma TME.ConclusionsGliomas employ FYN mediated mechanisms to enhance immune-suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of anti-glioma immunotherapies.Key pointsInhibition of FYN tyrosine kinase in genetically engineered mouse glioma models delays tumor initiation and progression. The oncogenic effects of FYN in vivo are mediated by downregulation of anti-glioma immunity.Importance of the StudyFYN is an effector of receptor tyrosine kinases (RTK) signaling in glioma. However, its role in vivo remains unknown. Our study demonstrates that FYN tyrosine kinase is a novel regulator of the anti-glioma immune response. We show that FYN inactivation suppresses glioma growth, increases survival, and enhances anti-tumor immune reactivity. Our findings suggest that suppressing the expression of FYN in glioma cells could provide a novel therapeutic target.

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Immature myeloid cells in the tumor microenvironment: Implications for immunotherapy

Cited by 42 publications

References 123 publications

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

Ratio of the interferon-γsignature to the immunosuppression signature predicts anti-PD-1 therapy response in melanoma

FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses

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