IL-3 signalling in the tumour microenvironment shapes the immune response via tumour endothelial cell-derived extracellular vesicles

Lopatina, Tatiana; Koni, Malvina; Grange, Cristina; Cedrino, Massimo; Femminò, Saveria; Lombardo, Giusy; Favaro, Enrica; Brizzi, Maria Felice

doi:10.1016/j.phrs.2022.106206

Cited by 15 publications

(8 citation statements)

References 37 publications

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“…We have recently shown that the EVs released by TEC upon IL-3Rα blockade modulate PD-L1 expression in myeloid cells [ 26 ]. Since cancer cells also express PD-L1, and its expression contributes to TNBC aggressiveness, PD-L1 was also evaluated in our in vivo model.…”

Section: Resultsmentioning

confidence: 99%

“…IL-3 was originally described as a haematopoietic factor [ 17 ]; however, IL-3, mainly released by tumour-infiltrating lymphocytes (TILs) [ 23 ], acts as a proinflammatory and proangiogenic cytokine [ 24 ]. Moreover, it has been shown that, in response to IL-3, tumour-derived endothelial cells (TECs) release extracellular vesicles (EVs) able to promote vessel growth [ 25 ], epithelial-to-mesenchymal transition (EMT), TNBC metastatic spread [ 22 ], and tumour immune evasion by upregulating the programmed cell death-ligand 1 (PD-L1) in myeloid cells [ 26 ]. All these data sustain the contribution of IL-3 signalling in the tumour microenvironment (TME).…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-3-Receptor-α in Triple-Negative Breast Cancer (TNBC): An Additional Novel Biomarker of TNBC Aggressiveness and a Therapeutic Target

Koni

Castellano

Venturelli

et al. 2022

Cancers

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Tumour molecular annotation is mandatory for biomarker discovery and personalised approaches, particularly in triple-negative breast cancer (TNBC) lacking effective treatment options. In this study, the interleukin-3 receptor α (IL-3Rα) was investigated as a prognostic biomarker and therapeutic target in TNBC. IL-3Rα expression and patients’ clinical and pathological features were retrospectively analysed in 421 TNBC patients. IL-3Rα was expressed in 69% human TNBC samples, and its expression was associated with nodal metastases (p = 0.026) and poor overall survival (hazard ratio = 1.50; 95% CI = 1.01–2.2; p = 0.04). The bioinformatics analysis on the Breast Invasive Carcinoma dataset of The Cancer Genome Atlas (TCGA) proved that IL-3Rα was highly expressed in TNBC compared with luminal breast cancers (p = 0.017, padj = 0.026). Functional studies demonstrated that IL-3Rα activation induced epithelial-to-endothelial and epithelial-to-mesenchymal transition, promoted large blood lacunae and lung metastasis formation, and increased programmed-cell death ligand-1 (PD-L1) in primary tumours and metastases. Based on the TCGA data, IL-3Rα, PD-L1, and EMT coding genes were proposed to discriminate against TNBC aggressiveness (AUC = 0.86 95% CI = 0.82–0.89). Overall, this study identified IL-3Rα as an additional novel biomarker of TNBC aggressiveness and provided the rationale to further investigate its relevance as a therapeutic target.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interleukin-3-Receptor-α in Triple-Negative Breast Cancer (TNBC): An Additional Novel Biomarker of TNBC Aggressiveness and a Therapeutic Target

Koni

Castellano

Venturelli

et al. 2022

Cancers

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“…TEV derived from TEC are involved in cancer development, metastatic spread and tumour immune editing [ 39 , 279 , 280 , 281 ]. TEC-derived TEV contain pro-oncogenic proteins and RNAs involved in immune regulation (TGFβ1, HLA-G, IL-6, M-CSF, as well as lncRNA MALAT1 and miR-24-3p) [ 39 , 279 , 280 ].…”

Section: Tev Released By Tme Cellsmentioning

confidence: 99%

“…TEC-derived TEV contain pro-oncogenic proteins and RNAs involved in immune regulation (TGFβ1, HLA-G, IL-6, M-CSF, as well as lncRNA MALAT1 and miR-24-3p) [ 39 , 279 , 280 ]. It has been shown that TEC-derived TEV enhance the expression of PD-L1 in tumour and myeloid cells, promote the formation of Treg and decrease T-cell cytotoxic activity [ 39 , 279 , 281 ]. Interestingly, stress conditions in the TME (hypoxia, inflammation, changes in the pH and many others) induce the release of TEV with specific tumour-promoting properties.…”

Section: Tev Released By Tme Cellsmentioning

confidence: 99%

Tumour Derived Extracellular Vesicles: Challenging Target to Blunt Tumour Immune Evasion

Lopatina

Sarcinella

Brizzi

2022

Cancers

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Control of the immune response is crucial for tumour onset and progression. Tumour cells handle the immune reaction by means of secreted factors and extracellular vesicles (EV). Tumour-derived extracellular vesicles (TEV) play key roles in immune reprogramming by delivering their cargo to different immune cells. Tumour-surrounding tissues also contribute to tumour immune editing and evasion, tumour progression, and drug resistance via locally released TEV. Moreover, the increase in circulating TEV has suggested their underpinning role in tumour dissemination. This review brings together data referring to TEV-driven immune regulation and antitumour immune suppression. Attention was also dedicated to TEV-mediated drug resistance.

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“…Some studies indicate induction of tumor-specific CD8+ T cells, while others have speculated that the effect might be conveyed through the inhibition of regulatory T cells. In addition, treatment with ipilimumab has been reported to reduce the frequency of MDSCs [98,99] . The long-term monitoring of Tregs, MDSCs, and tumor antigen responses at three, six, and nine months following treatment with ipilimumab resulted in several important findings.…”

Section: Role Of Myeloid Cells In Therapeutic Response To Immunotherapymentioning

confidence: 99%

Role of myeloid cells in the tumor microenvironment

Balakrishnan¹,

Vig²,

Dubey³

2022

J Cancer Metastasis Treat

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The dynamic interplay between tumor cells and immune cells in the microenvironment plays a crucial role in determining disease severity and therapeutic outcome in cancer. Myeloid cells are the most abundantly available cell population in the tumor microenvironment. Myeloid cells have been shown to exist in diverse phenotypes and play both antitumoral and protumoral roles in cancer. Understanding the biology of myeloid cells can lay the foundation for the development of therapeutic strategies aimed at enhancing the antitumoral role of myeloid cells. This article presents an overview of the role of myeloid cells in tumor development and various mechanisms by which myeloid cells aid tumor progression. Existing drugs against cancer that utilize myeloid cells and the role of myeloid cells in drug resistance are also discussed.

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IL-3 signalling in the tumour microenvironment shapes the immune response via tumour endothelial cell-derived extracellular vesicles

Cited by 15 publications

References 37 publications

Interleukin-3-Receptor-α in Triple-Negative Breast Cancer (TNBC): An Additional Novel Biomarker of TNBC Aggressiveness and a Therapeutic Target

Interleukin-3-Receptor-α in Triple-Negative Breast Cancer (TNBC): An Additional Novel Biomarker of TNBC Aggressiveness and a Therapeutic Target

Tumour Derived Extracellular Vesicles: Challenging Target to Blunt Tumour Immune Evasion

Role of myeloid cells in the tumor microenvironment

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