Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 9, Issue 2, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2020-002044
Keywords
killer cells; natural; immunity; innate; immune evation; immunologic surveillance; breast Neoplasms
Categories
Funding
- Brazilian Government under the Science without Borders Program [BEX 13446134]
- Science Foundation Ireland [13/CDA/2161]
- National Children's Research Center [A/18/5]
- Science Foundation Ireland (SFI) [13/CDA/2161] Funding Source: Science Foundation Ireland (SFI)
Ask authors/readers for more resources
Patients with metastatic breast cancer exhibit metabolic deficits in circulating NK cells, including reduced glycolysis and oxidative phosphorylation, as well as morphological alterations in mitochondria. Transforming growth factor-beta (TGFβ) is identified as a key driver of this phenotype. Blocking TGFβ and/or GARP can restore NK cell metabolism and function, presenting a novel target for improving NK cell-based immunotherapies.
Background Natural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to function optimally in a range of NK cell therapies, including those that depend on autologos circulating NK cells. We have previously demonstrated that NK cells undergo a normal metabolic reprogramming in response to cytokine activation and that this is required for optimal function. The objective of this work was to investigate if cellular metabolism of circulating NK cells is dysregulated in patients with metastatic breast cancer and if so, to gain insights into potential mechanisms underpinning this. Such discoveries would provide important insights into how to unleash the full activity of NK cells for maximum immunotherapy output. Methods Single-cell analysis, metabolic flux and confocal analysis of NK cells from patients with metastatic breast cancer and healthy controls Results In addition to reduced interferon-gamma production and cytotoxicity, peripheral blood NK cells from patients had clear metabolic deficits including reduced glycolysis and oxidative phosphorylation. There were also distinct morphologically alterations in the mitochondria with increased mitochondrial fragmentation observed. Transforminggrowth factor-beta (TGF beta) was identified as a key driver of this phenotype as blocking its activity reversed many metabolic and functional readouts. Expression of glycoprotein-A repetitions predominant (GARP) and latency associated peptide (LAP), which are involved with a novel TGF beta processing pathway, was increased on NK cells from some patients. Blocking the GARP-TGF beta axis recapitulated the effects of TGF beta neutralization, highlighting GARP as a novel NK cell immunotherapy target for the first time. Conclusions TGF beta contributes to metabolic dysfunction of circulating NK cells in patients with metastatic breast cancer. Blocking TGF beta and/or GARP can restore NK cell metabolism and function and is an important target for improving NK cell-based immunotherapies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available