Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human Vγ9Vδ2 T Cells

Rodrigues, Neidy Varela; Correia, Daniel V.; Mensurado, Sofia; Nóbrega-Pereira, Sandrina; deBarros, Ana; Kyle-Cezar, Fernanda; Tutt, Andrew; Hayday, Adrian; Norell, Haakan; Silva‐Santos, Bruno; Dias, Sérgio

doi:10.1158/2326-6066.cir-17-0327

Cited by 24 publications

(27 citation statements)

References 49 publications

(36 reference statements)

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“…Alternative therapies for TNBC are in great demand (40) and the impact of the TME on γδ T cells is of great interest to those wishing to further develop γδ T cell immunotherapy (31). For example, altered tumor cell metabolism was addressed in a recent study describing harmful effects of LDL cholesterol on Vδ2 γδ T cell cytokine production and cytotoxicity against MDA-MB-231 in vitro and in vivo, which may well occur in the TME (41). We previously found that while hypoxia activates γδ T cells, at the same time low oxygen serves to downregulate surface expression and/or increase shedding of MICA by breast cancer cell lines leading to less efficient target cell recognition (22).…”

Section: Discussionmentioning

confidence: 99%

Aberrantly Expressed Embryonic Protein NODAL Alters Breast Cancer Cell Susceptibility to γδ T Cell Cytotoxicity

et al. 2020

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Gamma delta (γδ) T cells kill transformed cells, and increased circulating γδ T cells levels correlate with improved outcome in cancer patients; however, their function within the breast tumor microenvironment (TME) remains controversial. As tumors progress, they begin to express stem-cell associated proteins, concomitant with the emergence of therapy resistant metastatic disease. For example, invasive breast cancers often secrete the embryonic morphogen, NODAL. NODAL has been shown to promote angiogenesis, therapy resistance and metastasis in breast cancers. However, to date, little is known about how this secreted protein may interact with cells in the TME. Herein we explore how NODAL in the TME may influence γδ T cell function. We have assessed the proximity of γδ T cells to NODAL in a cohort of triple negative breast tumors. In all cases in which γδ T cells could be identified in these tumors, γδ T cells were found in close proximity to NODAL-expressing tumor cells. Migration of γδ and αβ T cells was similar toward MDA-MB-231 cells in which NODAL had been knocked down (shN) and MDA-MB-231 scrambled control cells (shC). Furthermore, Vδ1 γδ T cells did not migrate preferentially toward conditioned medium from these cell lines. While 24-h exposure to NODAL did not impact CD69, PD-1, or T cell antigen receptor (TCR) expression on γδ T cells, long term exposure resulted in decreased Vδ2 TCR expression. Maturation of γδ T cells was not significantly influenced by NODAL stimulation. While neither short-nor long-term NODAL stimulation impacted the ability of γδ T cells to kill MCF-7 breast cancer cells, the absence of NODAL resulted in greater sensitivity of targets to γδ T cell cytotoxicity, while overexpression of NODAL conferred resistance. This appeared to be at least in part due to an inverse correlation between NODAL and surface MICA/B expression on breast cancer target lines. As such, it appears that NODAL may play a role in strategies employed by breast cancer cells to evade γδ T cell targeting, and this should be considered in the development of safe and effective γδ T cell immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Aberrantly Expressed Embryonic Protein NODAL Alters Breast Cancer Cell Susceptibility to γδ T Cell Cytotoxicity

et al. 2020

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“…Breast cancer cell lines (MDA-MB-231 - ATCC® HTB-26™, MCF7 - ATCC® HTB-22™), and the non-tumorigenic cell line MCF10A (gently provided by Sérgio Almeida Lab, IMM-JLA - ATCC® CRL-10317™) were all originally obtained from ATCC. MDA-231-GFP cells were produced from MDA-MB-231 pre-transduced with a lentiviral vector encoding luciferase and GFP, as previously described [19]. Breast cancer cell lines were routinely maintained in DMEM, containing 10% FBS and 2 mM L-Glutamine.…”

Section: Methodsmentioning

confidence: 99%

An antisense transcript mediates MALAT1 response in human breast cancer

et al. 2019

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Background Long non-coding RNAs (lncRNAs) represent a substantial portion of the human transcriptome. LncRNAs present a very stringent cell-type/tissue specificity being potential candidates for therapeutical applications during aging and disease. As example, targeting of MALAT1, a highly conserved lncRNA originally identified in metastatic non-small cell lung cancer, has shown promising results in cancer regression. Nevertheless, the regulation and specificity of MALAT1 have not been directly addressed. Interestingly, MALAT1 locus is spanned by an antisense transcript named TALAM1. Methods Here using a collection of breast cancer cells and in vitro and in vivo migration assays we characterized the dynamics of expression and demonstrated that TALAM1 regulates and synergizes with MALAT1 during tumorigenesis. Results Down-regulation of TALAM1 was shown to greatly impact on the capacity of breast cancer cells to migrate in vitro or to populate the lungs of immunocompromised mice. Additionally, we demonstrated that TALAM1 cooperates with MALAT1 in the regulation of the properties guiding breast cancer aggressiveness and malignancy. Conclusions By characterizing this sense/anti-sense pair we uncovered the complexity of MALAT1 locus regulation, describing new potential candidates for cancer targeting. Electronic supplementary material The online version of this article (10.1186/s12885-019-5962-0) contains supplementary material, which is available to authorized users.

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“…The inhibition of cholesterol biosynthesis with atorvastatin or 25-hydroxycholesterol regulates IL-10 production by inducing human CD4 + T cells to switch from an effector to an anti-inflammatory profile [ 60 ]. Furthermore, given the role of lipoproteins as cholesterol carriers, while they promote tumor growth by regulating T cell activation and functionality [ 61 ], recent studies have used them as anti-tumor drug delivery vehicles [ 62 ].…”

Section: Lipid Metabolism Impacts Immune Activation Against Tumor mentioning

confidence: 99%

Lipidomic-Based Advances in Diagnosis and Modulation of Immune Response to Cancer

Balgoma

Montero

2020

Metabolites

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While immunotherapies for diverse types of cancer are effective in many cases, relapse is still a lingering problem. Like tumor cells, activated immune cells have an anabolic metabolic profile, relying on glycolysis and the increased uptake and synthesis of fatty acids. In contrast, immature antigen-presenting cells, as well as anergic and exhausted T-cells have a catabolic metabolic profile that uses oxidative phosphorylation to provide energy for cellular processes. One goal for enhancing current immunotherapies is to identify metabolic pathways supporting the immune response to tumor antigens. A robust cell expansion and an active modulation via immune checkpoints and cytokine release are required for effective immunity. Lipids, as one of the main components of the cell membrane, are the key regulators of cell signaling and proliferation. Therefore, lipid metabolism reprogramming may impact proliferation and generate dysfunctional immune cells promoting tumor growth. Based on lipid-driven signatures, the discrimination between responsiveness and tolerance to tumor cells will support the development of accurate biomarkers and the identification of potential therapeutic targets. These findings may improve existing immunotherapies and ultimately prevent immune escape in patients for whom existing treatments have failed.

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Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human Vγ9Vδ2 T Cells

Cited by 24 publications

References 49 publications

Aberrantly Expressed Embryonic Protein NODAL Alters Breast Cancer Cell Susceptibility to γδ T Cell Cytotoxicity

Aberrantly Expressed Embryonic Protein NODAL Alters Breast Cancer Cell Susceptibility to γδ T Cell Cytotoxicity

An antisense transcript mediates MALAT1 response in human breast cancer

Lipidomic-Based Advances in Diagnosis and Modulation of Immune Response to Cancer

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