TGFβ drives mitochondrial dysfunction in peripheral blood NK cells during metastatic breast cancer

Slattery, Karen; Zaiatz-Bittencourt,; Woods, Elena; Brennan, Kiva; Marks, Sam Jonathan; Chew, Sonya; Conroy, Melissa J.; Goggin, Caitríona; Kennedy, J. S.; Finlay, David K.; Cm, Gardiner

doi:10.1101/648501

Cited by 11 publications

(13 citation statements)

References 30 publications

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“…Recent work from our lab showed that peripheral blood NK cells from patients with metastatic breast cancer have severely reduced levels of metabolism and impaired mTORC1 activity (54). Neutralization of TGFβ ex vivo restored levels of oxphos, mTORC1 activity, nutrient receptor expression and importantly, IFNγ production.…”

Section: Tgfβ and Nk Cell Metabolismmentioning

confidence: 92%

“…Excessive ROS may also result in aberrant cell signaling through oxidative modification of redox-sensitive signaling proteins e.g., MAPK, HIF or NFkB (70). Recent studies showed that excessive ROS production is associated with NK cell metabolic dysfunction in metastatic breast cancer patients and in childhood obesity (54,71). Interestingly, there is significant evidence demonstrating a connection between TGFβ and ROS production, with TGFβ treatment stimulating ROS production in many different studies.…”

Section: Tgfβ and Rosmentioning

confidence: 99%

“…Similarly, TGFβ has been shown to increase mitochondrial membrane potential in mouse kidney cells (83). Indeed, it is tempting to speculate that the increased mitochondrial mass and membrane potential observed in NK cells from metastatic breast cancer patients is in part due to increased TGFβ activity (54). In breast cancer cells, TGFβ has been shown to regulate expression of mitochondrial uncoupling protein 2 (UCP2), a mitochondrial transporter involved in dissipation of the mitochondria membrane potential to facilitate heat production (84).…”

Section: Tgfβ and Mitochondrial Structure And Functionmentioning

confidence: 99%

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NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

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NK cells are innate lymphocytes which play an essential role in protection against cancer and viral infection. Their functions are dictated by many factors including the receptors they express, cytokines they respond to and changes in the external environment. These cell processes are regulated within NK cells at many levels including genetic, epigenetic and expression (RNA and protein) levels. The last decade has revealed cellular metabolism as another level of immune regulation. Specific immune cells adopt metabolic configurations that support their functions, and this is a dynamic process with cells undergoing metabolic reprogramming during the course of an immune response. Upon activation with pro-inflammatory cytokines, NK cells upregulate both glycolysis and oxphos metabolic pathways and this supports their anti-cancer functions. Perturbation of these pathways inhibits NK cell effector functions. Anti-inflammatory cytokines such as TGFβ can inhibit metabolic changes and reduce functional outputs. Although a lot remains to be learned, our knowledge of potential molecular mechanisms involved is growing quickly. This review will discuss our current knowledge on the role of TGFβ in regulating NK cell metabolism and will draw on a wider knowledge base regarding TGFβ regulation of cellular metabolic pathways, in order to highlight potential ways in which TGFβ might be targeted to contribute to the exciting progress that is being made in terms of adoptive NK cell therapies for cancer.

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Section: Tgfβ and Nk Cell Metabolismmentioning

confidence: 92%

Section: Tgfβ and Rosmentioning

confidence: 99%

Section: Tgfβ and Mitochondrial Structure And Functionmentioning

confidence: 99%

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NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

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“…The tumor microenvironment contains large amounts of immunosuppressive cytokines and other soluble factors that affect NK cell functionality, with one of the most prominent being TGF-β (25). In addition to inducing downregulation of surface NKG2D, resulting in decreased cytotoxicity (26), TGF-β has been shown to be able to alter cytotoxicity, cytokine production, metabolism, and mitochondrial function in NK cells (27)(28)(29). Recent studies proposed that TGF-β also converts NK cells into noncytotoxic group 1 innate lymphoid cells (ILCs), allowing for tumor growth and metastasis in mice (30,31).…”

Section: Adoptive Nk Cell Therapymentioning

confidence: 99%

Killers 2.0: NK cell therapies at the forefront of cancer control

Hodgins

Khan

Park

et al. 2019

Journal of Clinical Investigation

165

127

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The existence of immune cells that mediate cellular cytotoxicity without prior activation was determined by multiple groups who reported the spontaneous killing of tumor cells by lymphocytes from unimmunized mice (1-3). We now know that these cells with natural cytotoxicity, or natural killer (NK) cells, are important mediators of cancer immunosurveillance. NK cells are a heterogeneous population, and in humans they have been historically divided into IFN-γ-producing CD56 hi CD16 + and cytotoxic CD56 lo CD16 hi (4), whereas in mice they are grouped according to their expression of CD27 and CD11b (5), although it is now clear that the complexity is much higher. Distinct NK cell subsets play different roles in tumor immunity and cancer immunotherapy, as reviewed in Stabile et al. (6). NK cells are equipped with many receptors that tightly regulate their activation and allow them to discriminate between "normal" and "dangerous" cells (7). In addition to regulating NK cell activation, signals coming from activating and inhibitory receptors also tune the steady-state responsiveness of NK cells to future stimuli, in a process called NK cell education (reviewed in refs. 8, 9). Inhibitory receptors, such as killer-cell immunoglobulinlike receptors (KIRs), deliver negative signals that prevent NK cell autoreactivity. KIRs and other inhibitory receptors recognize MHC I molecules, whose absence may result in NK activation, the so-called "missing-self recognition" (10, 11). Later studies showed that lack of MHC expression was not sufficient or necessary to induce NK activation; rather, signaling from activating receptors was required. Broadly speaking, activating receptors, including NKG2D, provide activating signals upon binding to stress-induced ligands on target cells, which is referred to as "induced-self recognition" (12, 13). Ultimately, NK activation depends on the balance between activating and inhibitory signals triggered by these receptors binding their ligands. When activating signals prevail, NK cells respond, whereas when inhibitory signaling is stronger, NK cells do not respond. Healthy cells, with some exceptions (14-16), express low levels of activating ligands and an abundance of inhibitory ligands and therefore are not attacked by NK cells. On the other hand, tumor cells often acquire expression of NK cellactivating ligands and/or lose expression of MHC molecules. NK cells sense and respond to changes in the repertoire of molecules expressed on the surface of healthy cells during cellular transformation. This positions NK cells as important sentinels against cancer and as prime targets for cancer immunotherapy (17).

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“…mTOR activity is required for increased glycolysis and mitochondrial functions during NK cell activation. Pharmacological inhibition of mTOR by rapamycin reduces the upregulation of glycolysis in mouse NK cells stimulated by IL-2/IL-12, and leads to a decrease in mitochondrial mass and membrane potential in human NK cells stimulated by IL-2, resulting in impaired effector functions ( 36 , 55 ). Consistently, CD56 bright NK cells that exhibit stronger metabolic responses to IL-2 or IL-12/IL-15 stimulation, have higher mTOR activity compared with CD56 dim NK cells ( 40 ); however, excessive activation of mTOR can cause mitochondrial fragmentation, thereby damaging mitochondrial function ( 37 ).…”

Section: Basic Nk Cell Metabolismmentioning

confidence: 99%

Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells

Cong

2020

Front. Immunol.

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Natural killer (NK) cells are the host's first line of defense against tumors and viral infections without prior sensitization. It is increasingly accepted that NK cells belong to the innate lymphoid cell (ILC) family. Other ILCs, comprising ILC1s, ILC2s, ILC3s and lymphoid tissue inducer (LTi) cells, are largely non-cytotoxic, tissue-resident cells, which function to protect local microenvironments against tissue insults and maintain homeostasis. Recently, evidence has accumulated that metabolism supports many aspects of the biology of NK cells and other ILCs, and that metabolic reprogramming regulates their development and function. Here, we outline the current understanding of ILC metabolism, and describe how metabolic processes are affected, and how metabolic defects are coupled to dysfunction of ILCs, in disease settings. Furthermore, we summarize the current and potential directions for immunotherapy involving targeting of ILC metabolism. Finally, we discuss the open questions in the rapidly expanding field of ILC metabolism.

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TGFβ drives mitochondrial dysfunction in peripheral blood NK cells during metastatic breast cancer

Cited by 11 publications

References 30 publications

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Killers 2.0: NK cell therapies at the forefront of cancer control

Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells

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