Nuclear receptor ligands induce TREM-1 expression on dendritic cells: analysis of their role in tumors

Fontana, Raffaella; Raccosta, Laura; Rovati, L; Steffensen, Knut R.; Paniccia, Aida; Jakobsson, Tomas; Melloni, Giulio; Bandiera, Alessandro; Mangili, Giorgia; Bergamini, Alice; Maggioni, Daniela; Doglioni, Claudio; Crocchiolo, Roberto; Cella, Marina; Mattioli, Michela; Battaglia, Cristina; Colonna, Marco; Russo, Vincenzo

doi:10.1080/2162402x.2018.1554967

Cited by 17 publications

(8 citation statements)

References 51 publications

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“…While TREM1-associated neutrophils and macrophages contribute to the immune-escape and metastasis of tumors, aberrant expression of TREM1 is also found in tumor cells themselves as well as in established cell lines and provides growth, survival, and migration advantages 44 . It has also been shown that in non-myeloid cells, TREM1 expression can be induced by nuclear receptor ligands 45 .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide CRISPR/Cas9 knockout screening uncovers a novel inflammatory pathway critical for resistance to arginine-deprivation therapy

et al. 2021

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Arginine synthesis deficiency due to the suppressed expression of ASS1 (argininosuccinate synthetase 1) represents one of the most frequently occurring metabolic defects of tumor cells. Arginine-deprivation therapy has gained increasing attention in recent years. One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors. The goal of this work is to identify novel factors conferring therapy resistance. Methods: Multiple, independently derived ADI-resistant clones including derivatives of breast (MDA-MB-231 and BT-549) and prostate (PC3, CWR22Rv1, and DU145) cancer cells were developed. RNA-seq and RT-PCR were used to identify genes upregulated in the resistant clones. Unbiased genome-wide CRISPR/Cas9 knockout screening was used to identify genes whose absence confers sensitivity to these cells. shRNA and CRISPR/Cas9 knockout as well as overexpression approaches were used to validate the functions of the resistant genes both in vitro and in xenograft models. The signal pathways were verified by western blotting and cytokine release. Results: Based on unbiased CRISPR/Cas9 knockout screening and RNA-seq analyses of independently derived ADI-resistant (ADIR) clones, aberrant activation of the TREM1/CCL2 axis in addition to ASS1 expression was consistently identified as the resistant factors. Unlike ADIR, MDA-MB-231 overexpressing ASS1 cells achieved only moderate ADI resistance both in vitro and in vivo , and overexpression of ASS1 alone does not activate the TREM1/CCL2 axis. These data suggested that upregulation of TREM1 is an independent factor in the development of strong resistance, which is accompanied by activation of the AKT/mTOR/STAT3/CCL2 pathway and contributes to cell survival and overcoming the tumor suppressive effects of ASS1 overexpression. Importantly, knockdown of TREM1 or CCL2 significantly sensitized ADIR toward ADI. Similar results were obtained in BT-549 breast cancer cell line as well as castration-resistant prostate cancer cells. The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. Conclusion: We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.

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Section: Discussionmentioning

confidence: 99%

Genome-wide CRISPR/Cas9 knockout screening uncovers a novel inflammatory pathway critical for resistance to arginine-deprivation therapy

et al. 2021

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“…TREM-1 involvement in NSCLC progression was further demonstrated by the finding that TREM-1 engagement by an agonist mAb in macrophages increased NSCLC's cell invasive ability, which was suppressed upon TREM-1 inhibition by shRNA [221]. TREM-1+ DCs accumulation in pleural effusions from patients with lung adenocarcinoma also seems to be associated with disease aggressiveness and bad prognosis [223].…”

Section: Trem-1 Role In Cancermentioning

confidence: 97%

Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1)

Raggi

Bosco

2020

Cancers

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Inflammatory cells are major players in the onset of cancer. The degree of inflammation and type of inflammatory cells in the tumor microenvironment (TME) are responsible for tilting the balance between tumor progression and regression. Cancer-related inflammation has also been shown to influence the efficacy of conventional therapy. Mononuclear phagocytes (MPs) represent a major component of the inflammatory circuit that promotes tumor progression. Despite their potential to activate immunosurveillance and exert anti-tumor responses, MPs are subverted by the tumor to support its growth, immune evasion, and spread. MP responses in the TME are dictated by a network of stimuli integrated through the cross-talk between activatory and inhibitory receptors. Alterations in receptor expression/signaling can create excessive inflammation and, when chronic, promote tumorigenesis. Research advances have led to the development of new therapeutic strategies aimed at receptor targeting to induce a tumor-infiltrating MP switch from a cancer-supportive toward an anti-tumor phenotype, demonstrating efficacy in different human cancers. This review provides an overview of the role of MP receptors in inflammation-mediated carcinogenesis and discusses the most recent updates regarding their targeting for immunotherapeutic purposes. We focus in particular on the TREM-1 receptor, a major amplifier of MP inflammatory responses, highlighting its relevance in the development and progression of several types of inflammation-associated malignancies and the promises of its inhibition for cancer immunotherapy.

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“…The GF9 peptide also attenuated tumour growth and prolonged survival in a model of pancreatic cancer 71 . Although TREM1 is mainly expressed in granulocytes and macrophages, it has been shown that TREM1 is induced in tumour-associated DCs through activation of the nuclear receptors RXR, RAR, LXR and VDR 72 . In patients with cancer, TREM1 was found in DCs from pleural effusions and ascites, which contain the LXR ligands such as oxysterols and the RXR ligand such as 9-cis retinoic acid; moreover, in vitro exposure of monocyte-derived DCs to tumour-conditioned fluids induced the expression of TREM1 together with LXR and RAR target genes.…”

Section: Trem1 Contributes To Cancer Inflammationmentioning

confidence: 99%

The biology of TREM receptors

Colonna

2023

Nat Rev Immunol

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137

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Triggering receptors expressed on myeloid cells (TREMs) encompass a family of cell-surface receptors chiefly expressed by granulocytes, monocytes and tissue macrophages. These receptors have been implicated in inflammation, neurodegenerative diseases, bone remodelling, metabolic syndrome, atherosclerosis and cancer. Here, I review the structure, ligands, signalling modes and functions of TREMs in humans and mice and discuss the challenges that remain in understanding TREM biology.

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Nuclear receptor ligands induce TREM-1 expression on dendritic cells: analysis of their role in tumors

Cited by 17 publications

References 51 publications

Genome-wide CRISPR/Cas9 knockout screening uncovers a novel inflammatory pathway critical for resistance to arginine-deprivation therapy

Genome-wide CRISPR/Cas9 knockout screening uncovers a novel inflammatory pathway critical for resistance to arginine-deprivation therapy

Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1)

The biology of TREM receptors

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