scholarly journals Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 874 ◽  
Author(s):  
Jiangang Zhao ◽  
Hans A. Schlößer ◽  
Zhefang Wang ◽  
Jie Qin ◽  
Jiahui Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Nk Cells ◽  
Extracellular Vesicles ◽  
Nk Cell ◽  
Killer Cell ◽  
Pancreatic Cancer Cell Line ◽  
Ductal Adenocarcinoma ◽  
Metastatic Niche ◽  
Niche Formation ◽  
Tgf Β1

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs’ TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs’ TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC.

scholarly journals Natural Killer Cell-Derived Extracellular Vesicles: Novel Players in Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Feifeng Wu ◽  
Min Xie ◽  
Marady Hun ◽  
Zhou She ◽  
Cuifang Li ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Extracellular Vesicles ◽  
Nk Cell ◽  
Biological Effects ◽  
Killer Cell ◽  
Immune Surveillance ◽  
Immunomodulatory Activity ◽  
Promising Tool

Natural killer (NK) cells are critical components of host innate immunity and function as the first line of defense against tumors and viral infection. There is increasing evidence that extracellular vesicles (EVs) are involved in the antitumor activity of NK cells. NK cell-derived EVs (NKEVs) carrying cargo such as cytotoxic proteins, microRNAs, and cytokines employ multiple mechanisms to kill tumor cells, but also exhibit immunomodulatory activity by stimulating other immune cells. Several studies have reported that NKEVs can reverse immune suppression under tolerogenic conditions and contribute to NK-mediated immune surveillance against tumors. Thus, NKEVs are a promising tool for cancer immunotherapy. In this review, we describe the biological effects and potential applications of NKEVs in antitumor immunity.

Expression of MICA/b, a ligand for natural killer (NK) cell recognition, on human pancreatic adenocarcinoma and potential for NK intervention.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 129-129
Author(s):  
Julie Djeu ◽  
Danielle Gilvary ◽  
Thu Le Trinh ◽  
Nhan Tu ◽  
Domenico Coppola
Keyword(s):  
Pancreatic Cancer ◽  
Nk Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Natural Killer ◽  
Cell Lines ◽  
Nk Cell ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cell ◽  
Pancreatic Cancer Cells

129 Background: Pancreatic cancer remains a leading cause of cancer-related mortality because of lack of means for early detection and notable refractoriness to standard chemotherapy in advanced stages of disease. Mobilization of the immune system is therefore an important option to explore. Natural Killer (NK) cells are potent effector cells in immune surveillance against cancer and offer a unique advantage because of expression of a C-type, lectin-like, type II transmembrane glycoprotein, NKG2D, on the cell surface. NKG2D is a receptor that specifically recognizes common stress-induced proteins such as MICA/B on tumor cells, targeting them for perforin/granzyme B-mediated destruction. The goal of this study is to examine if MICA/B is expressed on human pancreatic cancer cells, allowing the potential to direct immunotherapy against pancreatic cancer via NK cell therapy. Methods: This study was conducted under an IRB approved protocol. Pancreatic samples were taken from 121 patients with pancreatic ductal adenocarcinoma (PDA) and 103 cases of normal adjacent pancreatic tissues (NP) were included for comparison in a tissue microarray developed in the Tissue Core. All cases were stained for MICA/B AB using the Ventana automated immunostainer Discovery XT (Ventana,Tucson, AZ). Human pancreatic cell lines were also immunostained for MICA/B expression and tested for sensitivity to NK cell lysis in vitro. Results: A significant increase in MICA/B expression was observed during the progression from NP to PDA (p value < 0.0001) in pancreatic tumor tissues. Additionally, all pancreatic cell lines, including MiaPaca, Panc-1, and PCSC, express MICA/B and were readily lysed by NK cells. Conclusions: We report an increase in MICA/B expression during the progression of pancreatic ductal adenocarcinoma and MICA/B may represent a new immunotherapeutic target in pancreatic gastric carcinogenesis.

scholarly journals Extracellular Vesicles From the Human Natural Killer Cell Line NK3.3 Have Broad and Potent Anti-Tumor Activity

2021 ◽  
Vol 9 ◽  
Author(s):  
Allyson M. Cochran ◽  
Jacki Kornbluth
Keyword(s):  
Tumor Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Line ◽  
Extracellular Vesicles ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Natural Killer Cell ◽  
Large Numbers ◽  
Anti Tumor Activity

Natural killer (NK) cells are critical mediators of immune function, responsible for rapid destruction of tumor cells. They kill primarily through the release of granules containing potent cytolytic molecules. NK cells also release these molecules within membrane-bound exosomes and microvesicles – collectively known as extracellular vesicles (EV). Here we report the characterization and anti-tumor function of EVs isolated from NK3.3 cells, a well described clonal normal human NK cell line. We show that NK3.3 EVs contain the cytolytic molecules perforin, granzymes A and B, and granulysin, and an array of common EV proteins. We previously reported that the E3 ubiquitin ligase, natural killer lytic-associated molecule (NKLAM), is localized to NK granules and is essential for maximal NK killing; here we show it is present in the membrane of NK3.3 EVs. NK3.3-derived EVs also carry multiple RNA species, including miRNAs associated with anti-tumor activity. We demonstrate that NK3.3 EVs inhibit proliferation and induce caspase-mediated apoptosis and cell death of an array of both hematopoietic and non-hematopoietic tumor cell lines. This effect is tumor cell specific; normal cells are unaffected by EV treatment. By virtue of their derivation from a healthy donor and ability to be expanded to large numbers, NK3.3 EVs have the potential to be an effective, safe, and universal immunotherapeutic agent.

scholarly journals Understanding and Targeting Natural Killer Cell-Cancer-Associated Fibroblast Interactions in Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 405
Author(s):  
Zoe X. Malchiodi ◽  
Louis M. Weiner
Keyword(s):  
Natural Killer Cell ◽  
Nk Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Cancer ◽  
Killer Cell ◽  
Ductal Adenocarcinoma ◽  
Combination Regimen ◽  
Cancer Associated Fibroblast

Interactions between natural killer (NK) cells and cancer-associated fibroblasts (CAFs) comprise a relevant but relatively understudied crosstalk relationship within the tumor microenvironment (TME). This review discusses the relevance of both natural killer cell and cancer-associated fibroblast function and activity in cancers, with an emphasis on pancreatic ductal adenocarcinoma (PDAC), incorporating additional insights from other malignancies to inform future directions for research. We describe what is currently known about NK cell-CAF crosstalk and their molecular interactions, how it is possible to exploit NK cell cytotoxicity in tumors and how to target CAFs to enhance efficacy of cancer therapies and cytotoxic immune cells. Although not previously tested in combination, there is an abundance of evidence demonstrating that targeting tumor-promoting CAFs and exploiting NK cells, separately, are beneficial as therapeutic strategies. This raises the possibility that a novel combination regimen addressing these two cell targets may be even more beneficial to eradicate PDAC and other solid tumors.

scholarly journals The m15 Locus of Murine Cytomegalovirus Modulates Natural Killer Cell Responses to Promote Dissemination to the Salivary Glands and Viral Shedding

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 866
Author(s):  
Baca Chan ◽  
Maja Arapović ◽  
Laura Masters ◽  
Francois Rwandamuiye ◽  
Stipan Jonjić ◽  
...  
Keyword(s):  
Nk Cells ◽  
Salivary Glands ◽  
Natural Killer ◽  
Nk Cell ◽  
Acute Infection ◽  
Killer Cell ◽  
Viral Escape ◽  
Murine Cytomegalovirus ◽  
Viral Shedding ◽  
Cell Responses

As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as a viral modulator of natural killer (NK) cell immunity. We show that, rather than discrete transcripts from the m14, m15 and m16 genes as annotated, there are five 3′-coterminal transcripts expressed over this region, all utilising a consensus polyA tail at the end of the m16 gene. Functional inactivation of any one of these genes had no measurable impact on viral replication. However, disruption of all five transcripts led to significantly attenuated dissemination to, and replication in, the salivary glands of multiple strains of mice, but normal growth during acute infection. Disruption of the m15 locus was associated with heightened NK cell responses, including enhanced proliferation and IFNγ production. Depletion of NK cells, but not T cells, rescued salivary gland replication and viral shedding. These data demonstrate the identification of multiple transcripts expressed by a single locus which modulate, perhaps in a concerted fashion, the function of anti-viral NK cells.

scholarly journals Natural Killer Cell Mobilization in Breast and Prostate Cancer Survivors: The Implications of Altered Stress Hormones Following Acute Exercise

Endocrines ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 121-132
Author(s):  
Erik D. Hanson ◽  
Lauren C. Bates ◽  
Kaileigh Moertl ◽  
Elizabeth S. Evans
Keyword(s):  
Prostate Cancer ◽  
Immune System ◽  
Cancer Survivors ◽  
Nk Cells ◽  
Natural Killer ◽  
Acute Exercise ◽  
Nk Cell ◽  
Killer Cell ◽  
Current Evidence ◽  
Cell Mobilization

Natural killer (NK) cells from the innate immune system are integral to overall immunity and also in managing the tumor burden during cancer. Breast (BCa) and prostate cancer (PCa) are the most common tumors in U.S. adults. Both BCa and PCa are frequently treated with hormone suppression therapies that are associated with numerous adverse effects including direct effects on the immune system. Regular exercise is recommended for cancer survivors to reduce side effects and improve quality of life. Acute exercise is a potent stimulus for NK cells in healthy individuals with current evidence indicating that NK mobilization in individuals with BCa and PCa is comparable. NK cell mobilization results from elevations in shear stress and catecholamine levels. Despite a normal NK cell response to exercise, increases in epinephrine are attenuated in BCa and PCa. The significance of this potential discrepancy still needs to be determined. However, alterations in adrenal hormone signaling are hypothesized to be due to chronic stress during cancer treatment. Additional compensatory factors induced by exercise are reviewed along with recommendations on standardized approaches to be used in exercise immunology studies involving oncology populations.

scholarly journals Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2796
Author(s):  
Aicha E. Quamine ◽  
Mallery R. Olsen ◽  
Monica M. Cho ◽  
Christian M. Capitini
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Nk Cell ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Intensive Therapy ◽  
Killer Cell ◽  
Cell Therapies ◽  
Pediatric Solid Tumors

Treatment of metastatic pediatric solid tumors remain a significant challenge, particularly in relapsed and refractory settings. Standard treatment has included surgical resection, radiation, chemotherapy, and, in the case of neuroblastoma, immunotherapy. Despite such intensive therapy, cancer recurrence is common, and most tumors become refractory to prior therapy, leaving patients with few conventional treatment options. Natural killer (NK) cells are non-major histocompatibility complex (MHC)-restricted lymphocytes that boast several complex killing mechanisms but at an added advantage of not causing graft-versus-host disease, making use of allogeneic NK cells a potential therapeutic option. On top of their killing capacity, NK cells also produce several cytokines and growth factors that act as key regulators of the adaptive immune system, positioning themselves as ideal effector cells for stimulating heavily pretreated immune systems. Despite this promise, clinical efficacy of adoptive NK cell therapy to date has been inconsistent, prompting a detailed understanding of the biological pathways within NK cells that can be leveraged to develop “next generation” NK cell therapies. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors.

scholarly journals Role and Modulation of NK Cells in Multiple Myeloma

Hemato ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 167-181
Author(s):  
Marie Thérèse Rubio ◽  
Adèle Dhuyser ◽  
Stéphanie Nguyen
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Proteasome Inhibitors ◽  
Disease Evolution ◽  
Cell Functions

Myeloma tumor cells are particularly dependent on their microenvironment and sensitive to cellular antitumor immune response, including natural killer (NK) cells. These later are essential innate lymphocytes implicated in the control of viral infections and cancers. Their cytotoxic activity is regulated by a balance between activating and inhibitory signals resulting from the complex interaction of surface receptors and their respective ligands. Myeloma disease evolution is associated with a progressive alteration of NK cell number, phenotype and cytotoxic functions. We review here the different therapeutic approaches that could restore or enhance NK cell functions in multiple myeloma. First, conventional treatments (immunomodulatory drugs-IMids and proteasome inhibitors) can enhance NK killing of tumor cells by modulating the expression of NK receptors and their corresponding ligands on NK and myeloma cells, respectively. Because of their ability to kill by antibody-dependent cell cytotoxicity, NK cells are important effectors involved in the efficacy of anti-myeloma monoclonal antibodies targeting the tumor antigens CD38, CS1 or BCMA. These complementary mechanisms support the more recent therapeutic combination of IMids or proteasome inhibitors to monoclonal antibodies. We finally discuss the ongoing development of new NK cell-based immunotherapies, such as ex vivo expanded killer cell immunoglobulin-like receptors (KIR)-mismatched NK cells, chimeric antigen receptors (CAR)-NK cells, check point and KIR inhibitors.

Abstract WP319: miRNA Screening of Natural Killer Cell Identifies miR-1224 as a Post-Transcriptional Regulator of NK Cell Function After Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Yan Feng ◽  
Hui Zhao ◽  
Fu-Dong Shi ◽  
Weina Jin
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Nk Cells ◽  
Expression Profile ◽  
Mirna Expression ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Mirna Expression Profile ◽  
Control Group

Objectives: To screen miRNA profile of peripheral NK cells in ischemic stroke mouse model and investigate a most promising candidate (miR-1224) for post-transcriptional regulation of NK cell function after ischemic stroke. Methods: Mice were subjected to a 60 min focal cerebral ischemia produced by transient intraluminal occlusion of MCAO. For NK cell isolation, cell suspensions from the spleens after reperfusion were enriched for NK cells using magnetic-bead sorting system after staining with anti-NK1.1 microbeads. The nCounter Mouse miRNA array was used to analyze miRNA expression profile in splenic NK cells over the time course of experimental ischemic stroke. Based on the miRNA data, we further in vitro modulated miR-1224 in NK cells using mimics or inhibitor, then injected i.v into Rag2-/-γc-/- recipient mice. Neurological function score was compared and spontaneous infection was assessed by pulmonary bacteria colony culture, and changes in potential signaling pathway (SP1/TNF-α) were verified by rt-PCR and western blot. Results: Through miRNA expression profile analysis, we have identified significant changes at each time point in peripheral NK cells after cerebral ischemia. Among all screened miRNA, miR-1224 remarkably increased in MCAO group, which was verified by PCR. Then isolated NK cells treated with mimics or inhibitors, were transferred to Rag2-/-γc-/- recipient mice. Compared with WT mice, Rag2-/-γc-/- mice with miR-1224 inhibitor exhibited increased NK cell number, enhanced NK cell activation/cytotoxicity feature, as well as better neurological behaviors and reduced pulmonary infection after MCAO. Moreover, compared with the control group, NK cells with miR-1224 inhibitor showed significantly increased SP1 gene and protein phosphorylation. As SP1 gene is one of the potential targets of miR-1224, this study suggests that miR-1224 may regulate NK cell function after MCAO, which is associated with SP1 pathway. Conclusion: The miRNA profiling of splenic NK cells provided insight into the functional mechanism and signaling pathways underlying the distinct organ-specific NK cell properties, which will contribute to the better understanding of NK cell mediated immune-response in relation to different stages of stroke.

Sign in / Sign up

Export Citation Format

Share Document