Exosomal lncRNA SNHG10 derived from colorectal cancer cells suppresses natural killer cell cytotoxicity by upregulating INHBC

Abstract Background Exosome-mediated crosstalk between cancer cells and immune cells contributes to tumor growth. In this study, we investigated the mechanism underlying the exosome-mediated immune escape of colorectal cancer (CRC) cells from natural killer (NK) cells via the transfer of long noncoding RNAs (lncRNAs). Methods An epithelial–mesenchymal transition (EMT) model of SW480 cells was established by transforming growth factor beta (TGF-β), followed by the assessment of the effect of EMT-derived exosomes (EMT-exo) on the functions of NK cells. RNA sequencing was performed to identify exosomal lncRNAs and target genes. The function of exosomal lncRNAs in tumor growth was further verified in vivo. Results EMT-exo suppressed the proliferation, cytotoxicity, IFN-γ production, and perforin-1 and granzyme B secretion of NK cells. RNA sequencing revealed that SNHG10 expression was upregulated in EMT-exo compared with that in non-EMT-exo. Moreover, SNHG10 expression was upregulated in tumor tissues in CRC, which was associated with poor prognosis. Overexpression of SNHG10 in exosomes (oe-lnc-SNHG10 exo) significantly suppressed the viability and cytotoxicity of NK cells. Transcriptome sequencing of NK cells revealed that the expression levels of 114 genes were upregulated in the oe-lnc-SNHG10 exo group, including inhibin subunit beta C (INHBC), which was involved in the TGF-β signaling pathway. Si-INHBC treatment abrogated the effect of oe-lnc-SNHG10 exo on NK cells. oe-lnc-SNHG10 exo induced tumor growth and upregulated INHBC expression in mice and downregulated the expression of perforin, granzyme B, and NK1.1 in tumor tissues. Conclusions The CRC cell-derived exosomal lncRNA SNHG10 suppresses the function of NK cells by upregulating INHBC expression. This study provides evidence that exosomal lncRNAs contribute to immune escape by inducing NK cell inhibition and proposes a potential treatment strategy for CRC.

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α-Pinene Enhances the Anticancer Activity of Natural Killer Cells via ERK/AKT Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22020656 ◽

2021 ◽

Vol 22 (2) ◽

pp. 656

Author(s):

Hantae Jo ◽

Byungsun Cha ◽

Haneul Kim ◽

Sofia Brito ◽

Byeong Mun Kwak ◽

...

Keyword(s):

Nk Cells ◽

Cancer Cells ◽

Natural Killer ◽

Nk Cell ◽

Granzyme B ◽

Akt Pathway ◽

Cell Cytotoxicity ◽

Anticancer Effects ◽

Nk Cell Cytotoxicity

Natural killer (NK) cells are lymphocytes that can directly destroy cancer cells. When NK cells are activated, CD56 and CD107a markers are able to recognize cancer cells and release perforin and granzyme B proteins that induce apoptosis in the targeted cells. In this study, we focused on the role of phytoncides in activating NK cells and promoting anticancer effects. We tested the effects of several phytoncide compounds on NK-92mi cells and demonstrated that α-pinene treatment exhibited higher anticancer effects, as observed by the increased levels of perforin, granzyme B, CD56 and CD107a. Furthermore, α-pinene treatment in NK-92mi cells increased NK cell cytotoxicity in two different cell lines, and immunoblot assays revealed that the ERK/AKT pathway is involved in NK cell cytotoxicity in response to phytoncides. Furthermore, CT-26 colon cancer cells were allografted subcutaneously into BALB/c mice, and α-pinene treatment then inhibited allografted tumor growth. Our findings demonstrate that α-pinene activates NK cells and increases NK cell cytotoxicity, suggesting it is a potential compound for cancer immunotherapy.

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Antitumor Activity of Polysaccharides Extracted from the Spore Powder of Ganoderma Lucidum (Fr.) Karst

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.17:394-400 ◽

2019 ◽

Vol 17 (4) ◽

pp. 394-400

Author(s):

Wu Jiadi ◽

Fei Dongliang ◽

Fu Chenghao ◽

Jiang Chunying ◽

Zhao Yan ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Growth ◽

Nk Cells ◽

Cancer Cells ◽

Ganoderma Lucidum ◽

Nk Cell ◽

Granzyme B ◽

Cell Numbers ◽

Low Toxicity ◽

4T1 Cells

Ganoderma lucidum (Fr.) Karst. has attracted much attention for its antitumor activity and low toxicity. In fact, the spores of G. lucidum may have even higher bioactivity than its fruiting body. However, there is no report on how the polysaccharides from broken spores of G. lucidum may suppress tumor growth. To make up for this gap, this article isolates a type of polysaccharide from the spore powder of G. lucidum and explores its effect on tumor growth in mice bearing 4T1 cells. The results show that the spore powder of G. lucidum could inhibit the tumor growth of 4T1-bearing mice by increasing NK cell numbers in two ways. First, the spore powder of G. lucidum suppresses Tregs to increase the percentage of NK cells, thus killing cancer cells in blood. Second, the spore powder of G. lucidum upregulates the expression of CXCR3, which recruits more NK cells from peripheral blood infiltrating in visceral organs, where NK cells secrete more granzyme B, perforin, and interferon gamma to kill cancer cells. To sum up, our research demonstrates the potential of spore powder of G. lucidum in cancer therapy.

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Radiotherapy-induced overexpression of exosomal miRNA-378a-3p in cancer cells limits natural killer cells cytotoxicity

Epigenomics ◽

10.2217/epi-2019-0193 ◽

2020 ◽

Vol 12 (5) ◽

pp. 397-408 ◽

Cited By ~ 3

Author(s):

Joséphine Briand ◽

Delphine Garnier ◽

Arulraj Nadaradjane ◽

Karen Clément-Colmou ◽

Vincent Potiron ◽

...

Keyword(s):

Nk Cells ◽

Cancer Cells ◽

Natural Killer ◽

Granzyme B ◽

Inverse Correlation ◽

Molecular Signature ◽

Mice Model ◽

Blood Samples ◽

Human Blood Samples ◽

Exosomal Mirna

Aim: We here hypothesized that tumor-derived exosomal miRNA (TexomiR) released from irradiated tumors may play a role in the tumor cells escape to natural killer (NK) cells. Materials & methods: Our study included the use of different cancer cell lines, blood biopsies of xenograph mice model and patients treated with radiotherapy. Results: The irradiation of cancer cells promotes the TET2-mediated demethylation of miR-378 promoter, miR-378a-3p overexpression and its loading in exosomes, inducing the decrease of granzyme-B (GZMB) secretion by NK cells. An inverse correlation between TexomiR-378a-3p and GZMB was observed in murine and human blood samples. Conclusion: Our work identifies TexomiR-378a-3p as a molecular signature associated with the loss of NK cells cytotoxicity via the decrease of GZMB expression upon radiotherapy.

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A regulatory loop among CD276, miR-29c-3p, and Myc exists in cancer cells against natural killer cell cytotoxicity

Life Sciences ◽

10.1016/j.lfs.2021.119438 ◽

2021 ◽

Vol 277 ◽

pp. 119438

Author(s):

Chin-Cheng Lee ◽

Kuo-Hao Ho ◽

Tzu-Wen Huang ◽

Chwen-Ming Shih ◽

Shao-Yuan Hsu ◽

...

Keyword(s):

Natural Killer Cell ◽

Cancer Cells ◽

Natural Killer ◽

Killer Cell ◽

Cell Cytotoxicity ◽

Natural Killer Cell Cytotoxicity ◽

Regulatory Loop

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RNA-sequencing identified miR-3681 as a negative regulator in the proliferation and migration of cervical cancer cells via the posttranscriptional suppression of HGFR

RSC Advances ◽

10.1039/c9ra01785b ◽

2019 ◽

Vol 9 (39) ◽

pp. 22376-22383 ◽

Cited By ~ 1

Author(s):

Fan Shi ◽

Yingbing Zhang ◽

Juan Wang ◽

Jin Su ◽

Zi Liu ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Rna Sequencing ◽

Negative Regulator ◽

Tumor Tissues ◽

Differentially Expressed Mirnas ◽

Cervical Cancer Cells ◽

And Migration ◽

Cancer Tissues ◽

Proliferation And Migration

In this study, RNA-sequencing was used to investigate the differentially expressed miRNAs between cervical cancer tissues and matched adjacent non-tumor tissues.

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736 Treatment with decitabine (DAC) induces the expression of stemness markers, PD-L1 and NY-ESO-1 in colorectal cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.736 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A767-A767

Author(s):

Nassiba Taib ◽

Maysaloun Merhi ◽

Varghese Inchakalody ◽

Sarra Mestiri ◽

Afsheen Raza ◽

...

Keyword(s):

Colorectal Cancer ◽

New York ◽

Colon Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Tumor Antigen ◽

Immune Escape ◽

Combined Treatment ◽

Cpg Islands ◽

Dna Demethylation

BackgroundColorectal cancer (CRC) is a leading cause of cancer related deaths. Epigenetic silencing of numerous tumor suppressor genes by promoter region hypermethylation has been found in a variety of cancers including CRC. The chemotherapeutic drug decitabine (DAC) is a strong inducer of DNA demethylation. Primary cancer cells are known to express stemness markers as an escape pathway of treatment. Moreover, immunoregulatory genes can be inactivated in these cells by methylation of promoter CpG islands. Both mechanisms are known to play crucial roles in tumor progression. In this study, we investigated the effect of DAC on the expression of stemness markers, Programmed cell death ligand (PD-L1) and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) in a metastatic (1872 Col) and a primary (1076 Col) colorectal cancer cell lines isolated from patients' tumor tissues.MethodsThe 1076 Col and 1872 Col cell lines were treated with 5 μM of DAC for 48 hours. Differential expression of a panel of stemness and immunoregulatory markers before and after treatment was analyzed by Flow cytometry (FACS), Western Blotting (WB) and quantitative real time PCR (qRT-PCR).ResultsThe following stemness markers: CD44, Nanog, KLF-4, CD133 and MSI1 were up-regulated in both 1076 Col and 1872 Col cell lines after treatment. However, significant up-regulation of the immunoinhibitory PD-L1 marker was recorded after treatment only in the metastatic 1872 Col. Interestingly, the NY-ESO-1 tumor antigen was significantly upregulated in both 1076 Col and 1872 Col cell lines after treatment.ConclusionsTreatment of colon cancer cells with DAC induces chemotherapeutic resistance as evidenced by the induction/upregulation of the stemness markers; and immune escape mechanism through the induction/upregulation of PD-L1. However, such treatment resulted in the induction/expression of the most immunogenic NY-ESO-1 tumor antigen. Our data suggest the importance use of a combined treatment strategy utilizing chemotherapy (DAC) with anti-PD-L-1/PD-1treatment in colon cancer patients.Ethics ApprovalThe study obtained ethical approval from Hamad Medical Corporation, Medical Research Center Ethic Board: Grant ID : IRGC-04-SI-17-142.

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Abstract 046: The Role of Tumor Necrosis Factor α and Natural Killer Cells in Uterine Artery Function During Pregnancy in the Stroke Prone Spontaneously Hypertensive Rat

Hypertension ◽

10.1161/hyp.68.suppl_1.046 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Heather Y Small ◽

Ryszard Nosalski ◽

Hannah Morgan ◽

Elisabeth Beattie ◽

Tomasz Guzik ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Uterine Artery ◽

Spontaneously Hypertensive Rat ◽

Granzyme B ◽

Causative Role ◽

Maternal Circulation ◽

Etanercept Treatment ◽

Spontaneously Hypertensive ◽

Hypertensive Rat

Objective: We have previously characterised the stroke prone spontaneously hypertensive rat (SHRSP) as a model of deficient uterine artery remodelling and identified an increase in pro-inflammatory TNFα relative to the normotensive WKY strain during pregnancy. Method: SHRSP were treated with etanercept (0.8 mg/kg) or vehicle at gestational day (GD) 0, 6, 12 and 18. Animals were sacrificed at GD18. Results: Etanercept reduced systolic blood pressure in the SHRSP after GD12 (ΔSBP GD 10-21 SHRSP 12.0 ± 4.17 vs. ETN 25.8 ± 4.27 mmHg; p<0.05). Uterine arteries from GD18 showed that etanercept reduced uterine artery contraction (SHRSP 57.3 ± 8.75 vs. ETN 35.2 ± 2.19 kPa; p<0.01) and increased carbachol response (SHRSP 13.8 ± 3.8 vs. ETN 40.1 ± 3.25 %; p<0.05). Uteroplacental blood flow analysed using Doppler showed that etanercept reduced uterine artery resistance index in SHRSP (SHRSP 0.79 ± 0.02 vs. ETN 0.61 ± 0.02 UARI; p<0.01). Etanercept increased litter size (SHRSP 7.80 ± 0.44 vs. ETN 12.75 ± 0.94 fetuses), reduced resorption frequency (SHRSP 66.7% vs. ETN 25.0% dams with resorption) and decreased glycogen cell loss from the placenta in SHRSP. We sought to identify the source of excess TNFα in the SHRSP. Natural killer (NK) cells (CD3-CD161+) were increased in the SHRSP relative to the WKY in the maternal circulation (WKY 1.5 ± 0.4 vs. SHRSP 6.06 ± 0.28 %; p<0.01) and placenta (WKY 11.6 ± 2.39 vs. SHRSP 659.8 ± 201.2 cells/mg; p<0.01). These NK cells produced excess TNFα in the SHRSP maternal circulation (SHRSP 6.5 ± 0.4 vs. WKY 2.5 ± 0.4 %; p<0.05) and placenta (SHRSP 65.7 ± 4.2 vs. WKY 16.9 ± 1.7 %; p<0.01) relative to the WKY. In the SHRSP placenta, etanercept treatment reduced the number of cytotoxic NK cells (SHRSP 659.8 ± 201.2 vs. ETN 148.0 ± 12.62 cells/mg; p<0.01) by down-regulating CD161 expression associated with a decrease in granzyme B production (CD161+ 71.47 ± 2.1 vs. CD161 Low 14.32 ± 0.77 % granzyme B+; p<0.01). Conclusions: Excess TNFα plays a causative role in adverse pregnancy outcome in the SHRSP. One source of this TNFα is an increase in NK cells during gestation in the SHRSP. Etanercept targets NK cells in the SHRSP placenta and down-regulates cytotoxic granzyme B production.

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NATURAL KILLER (NK) CELLS: CHARACTERISTICS AND POSSIBLE ROLE IN RESISTANCE AGAINST TUMOR GROWTH

Immunity to Cancer ◽

10.1016/b978-0-12-586270-7.50024-0 ◽

1985 ◽

pp. 217-229 ◽

Cited By ~ 8

Author(s):

Ronald B. Herberman

Keyword(s):

Tumor Growth ◽

Nk Cells ◽

Natural Killer

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The Effects of Mesenchymal Stem Cells on Antimelanoma Immunity Depend on the Timing of Their Administration

Stem Cells International ◽

10.1155/2020/8842659 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Dragana Miloradovic ◽

Dragica Miloradovic ◽

Bojana Simovic Markovic ◽

Aleksandar Acovic ◽

Carl Randall Harrell ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Lymphocytes ◽

Tumor Growth ◽

Nk Cells ◽

Plasma Levels ◽

Th17 Cells ◽

Antitumor Immunity ◽

Granzyme B ◽

Lower Plasma

There is still a lively debate about whether mesenchymal stem cells (MSCs) promote or suppress antitumor immune response. Although several possible explanations have been proposed, including different numbers of injected and engrafted MSCs, heterogeneity in phenotype, and function of tumor cells, the exact molecular mechanisms responsible for opposite effects of MSCs in modulation of antitumor immunity are still unknown. Herewith, we used a B16F10 murine melanoma model to investigate whether timing of MSC administration in tumor-bearing mice was crucially important for their effects on antitumor immunity. MSCs, intravenously injected 24 h after melanoma induction (B16F10+MSC1d-treated mice), significantly enhanced natural killer (NK) and T cell-driven antitumor immunity, suppressed tumor growth, and improved survival of melanoma-bearing animals. Significantly higher plasma levels of antitumorigenic cytokines (TNF-α and IFN-γ), remarkably lower plasma levels of immunosuppressive cytokines (TGF-β and IL-10), and a significantly higher number of tumor-infiltrating, IFN-γ-producing, FasL- and granzyme B-expressing NK cells, IL-17-producing CD4+Th17 cells, IFN-γ- and TNF-α-producing CD4+Th1 cells, and CD8+cytotoxic T lymphocytes (CTLs) were observed in B16F10+MSC1d-treated mice. On the contrary, MSCs, injected 14 days after melanoma induction (B16F10+MSC14d-treated mice), promoted tumor growth by suppressing antigen-presenting properties of tumor-infiltrating dendritic cells (DCs) and macrophages and by reducing tumoricidal capacity of NK cells and T lymphocytes. Significantly higher plasma levels of TGF-β and IL-10, remarkably lower plasma levels of TNF-α and IFN-γ, and significantly reduced number of tumor-infiltrating, I-A-expressing, and IL-12-producing macrophages, CD80- and I-A-expressing DCs, granzyme B-expressing CTLs and NK cells, IFN-γ- and IL-17-producing CTLs, CD4+Th1, and Th17 cells were observed in B16F10+MSC14d-treated animals. In summing up, the timing of MSC administration into the tumor microenvironment was crucially important for MSC-dependent modulation of antimelanoma immunity. MSCs transplanted during the initial phase of melanoma growth exerted tumor-suppressive effect, while MSCs injected during the progressive stage of melanoma development suppressed antitumor immunity and enhanced tumor expansion.

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