Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy

Correia, Ana Luísa; Guimaraes, Joao C.; Maur, Priska Auf der; Silva, Duvini De; Trefny, Marcel P.; Okamoto, Ryoko; Bruno, Sandro; Schmidt, Alexander; Mertz, Kirsten D.; Volkmann, Katrin; Terracciano, Luigi; Zippelius, Alfred; Vetter, Marcus; Kurzeder, Christian; Weber, Walter; Bentires‐Alj, Mohamed

doi:10.1038/s41586-021-03614-z

Cited by 156 publications

(113 citation statements)

References 61 publications

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“…In addition to their direct cytolytic function, NK cells promote optimal CD8+ T cell responses via release of tumor antigens, recruitment and maturation of dendritic cells, as well as IFNγ mediated upregulation of MHC I expression ( 6 , 7 ). Furthermore, IFNγ production by NK cells has also recently been shown to sustain dormancy of liver metastases ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

et al. 2021

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Selinexor is an FDA approved selective inhibitor of the nuclear export protein exportin-1 (XPO1) and causes specific cancer cell death via nuclear accumulation of tumor suppressor proteins. Design of rational studies for the use of selinexor in combination with other therapeutic agents, such as immunotherapies, requires a fundamental understanding of the effects of selinexor on the immune system. One important emerging area of immunotherapy are natural killer (NK) cell based therapeutics. NK cell function is tightly regulated by a balance of signals derived from multiple activating and inhibitory receptors. Thus in cancer, up-regulation of stress ligands recognised by activating receptors or down-regulation of HLA class I recognised by inhibitory receptors can result in an anti-cancer NK cell response. Changes in XPO1 function therefore have the potential to affect NK cell function through shifting this balance. We therefore sought to investigate how selinexor may affect NK cell function. Selinexor pre-treatment of lymphoma cells significantly increased NK cell mediated cytotoxicity against SU-DHL-4, JeKo-1 and Ramos cells, concurrent with increased CD107a and IFNγ expression on NK cells. In addition, selinexor enhanced ADCC against lymphoma cells coated with the anti-CD20 antibodies rituximab and obinutuzumab. In probing the likely mechanism, we identified that XPO1 inhibition significantly reduced the surface expression of HLA-E on lymphoma cell lines and on primary chronic lymphocytic leukemia cells. HLA-E binds the inhibitory receptor NKG2A and in accordance with this, selinexor selectively increased activation of NKG2A+ NK cells. Our data reveals that selinexor, in addition to its direct cytotoxic activity, also activates an anti-cancer immune response via disruption of the inhibitory NKG2A:HLA-E axis.

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Section: Introductionmentioning

confidence: 99%

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

et al. 2021

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“…LDRT, by breaking the stroma barrier and modulating the TME, can enhance effector T cells activity and persistence that is required for successful CPI and ACT. A recent study showed that the activation of NK cells can be suppressed by HSCs ( 38 ). Thus, an NK cell-stimulating treatment such as IL-15 may further augment the antitumor effect of LDRT to liver metastases.…”

Section: Low-dose Radiotherapy (Ldrt) For Liver Metastasesmentioning

confidence: 99%

Novel Use of Low-Dose Radiotherapy to Modulate the Tumor Microenvironment of Liver Metastases

Barsoumian

Bertolet

et al. 2021

Front. Immunol.

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Despite multiple therapeutic approaches, the presence of liver metastases carries a guarded prognosis, urgently necessitating further clinical and scientific research to develop curative interventions. The liver is an immunoprivileged organ that suppresses the effectiveness of immunotherapies in patients with hepatic metastases. Cancer immunotherapies have been successfully bolstered by low-dose radiotherapy (LDRT), which is capable of reprogramming the tumor microenvironment (TME) from an immunosuppressive to an immunostimulatory one. Likewise, LDRT may be able to revoke the immune privilege enjoyed by the liver, permitting successful immunotherapies there. Here, we first review challenges that face the treatment of liver metastases. We next outline emerging preclinical and clinical evidence supporting enhanced systemic tumor control of LDRT in the context of cancer immunotherapy. Finally, we will discuss the rationale of combining liver-directed LDRT with immunostimulatory strategies to overcome immune resistance and achieve better clinical response. This notion is supported by a recent case study in which a patient who had progressed following T cell therapy experienced a complete response after LDRT to the liver.

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“…These cells present a secretory phenotype that allow them to mediate in the immune surveillance and inflammation, such as the ligand for NK cell receptors MCP1, facilitating the removal of quiescent HSCs. But they also help in the resolution of fibrosis as they diminish the secretion and expression of ECM proteins [ 5 , 83 , 86 , 87 ]. However, it is not clear yet why these active HSCs escape cell death and acquire a senescent quiescent-like phenotype, allowing them to be incorporated to the restored tissue [ 83 ].…”

Section: Hsc-dependent Molecular Mechanism Of Liver Fibrosismentioning

confidence: 99%

Metabolic Reprogramming of Liver Fibrosis

Delgado

Cárdenas

Farran

et al. 2021

Cells

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Liver fibrosis is an excessive and imbalanced deposition of fibrous extracellular matrix (ECM) that is associated with the hepatic wound-healing response. It is also the common mechanism that contributes to the impairment of the liver function that is observed in many chronic liver diseases (CLD). Despite the efforts, no effective therapy against fibrosis exists yet. Worryingly, due to the growing obesity pandemic, fibrosis incidence is on the rise. Here, we aim to summarize the main components and mechanisms involved in the progression of liver fibrosis, with special focus on the metabolic regulation of key effectors of fibrogenesis, hepatic stellate cells (HSCs), and their role in the disease progression. Hepatic cells that undergo metabolic reprogramming require a tightly controlled, fine-tuned cellular response, allowing them to meet their energetic demands without affecting cellular integrity. Here, we aim to discuss the role of ribonucleic acid (RNA)-binding proteins (RBPs), whose dynamic nature being context- and stimuli-dependent make them very suitable for the fibrotic situation. Thus, we will not only summarize the up-to-date literature on the metabolic regulation of HSCs in liver fibrosis, but also on the RBP-dependent post-transcriptional regulation of this metabolic switch that results in such important consequences for the progression of fibrosis and CLD.

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Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy

Cited by 156 publications

References 61 publications

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

Novel Use of Low-Dose Radiotherapy to Modulate the Tumor Microenvironment of Liver Metastases

Metabolic Reprogramming of Liver Fibrosis

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