scholarly journals Gastric Cancer Mesenchymal Stem Cells Inhibit NK Cell Function through mTOR Signalling to Promote Tumour Growth

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Shuwei Guo ◽  
Chao Huang ◽  
Fengfeng Han ◽  
Bin Chen ◽  
Ying Ding ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Nk Cells ◽  
Tumour Growth ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Study Results ◽  
Mtor Signalling

The dysfunction of natural killer (NK) cells has been increasingly reported in malignancies, especially in solid tumours. Mesenchymal stem cells (MSCs) exhibit pleiotropic functions that include mediating immune cell exhaustion which is implicated in cancer progression. However, the association of MSCs derived from gastric cancer (gastric cancer mesenchymal stem cells: GCMSCs) with the dysfunction of NK cells remains poorly understood. In this study, we demonstrated that GCMSCs effectively contributed to the exhaustion of NK cells through the release of soluble factors. Furthermore, passivation of the antitumour effect in NK cells was closely associated with their dysfunctional state. The GCMSC-conditioned medium prevented the frequency and effector function of infiltrating NK cells in tumour-bearing mouse models, thus promoting tumour growth. Mechanistically, mammalian target of rapamycin (mTOR) signalling, a critical regulator of cellular metabolism that mediates the function of immune cells, was inhibited in NK cells treated with GCMSCs. However, the checkpoint receptor PD-1 was still present at minimal levels with or without GCMSCs. The study results revealed that GCMSCs contributed to dysfunctional NK cells involved at least partially in the inhibition of mTOR signalling, suggesting potential directions for NK cell-based cancer immunotherapy.

scholarly journals The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF

2019 ◽  
Vol 216 (9) ◽  
pp. 2010-2023 ◽  
Author(s):  
Jessica Vetters ◽  
Mary J. van Helden ◽  
Sigrid Wahlen ◽  
Simon J. Tavernier ◽  
Arne Martens ◽  
...  
Keyword(s):  
Cell Death ◽  
Nk Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Homeostasis ◽  
Life And Death ◽  
Cytotoxic Molecules ◽  
Editing Enzyme ◽  
Mtor Activity

The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20−/− cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20−/− cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.

Evidence for Killing of Mesenchymal Stem Cells (MSC) by Autologous Natural Killer Lymphocytes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1290-1290 ◽  
Author(s):  
Alessandro Poggi ◽  
Anna-Maria Massaro ◽  
Simone Negrini ◽  
Ivana Pierri ◽  
Manuela Balocco ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Natural Killer ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Lineage ◽  
Culture Conditions ◽  
Inhibitory Receptors

Abstract In this study, Mesenchymal Stem Cells (MSC) were obtained from bone marrow of 10 patients suffering from acute myeloid leukemia (AML), six M0/1 two M2, and two M5 (according to the FAB classification), 8 out of 10 in post-chemotherapy complete remission. These cells differentiated into adipocytes or osteoblasts under appropriate culture conditions. MSC were CD44+, CD73a+ CD73b+ CD105+, beta1 integrin+, ICAM1+, HLA-I+, HLA-II+ (variable proportions), CD45−, CD31−, CD34− and they constitutively expressed the stress-inducible MHC-related molecules MIC-A and the UL16 (induced at the surface of cells infected by cytomegalovirus) binding protein ULBP3. These molecules are reported ligands for the NKG2D receptor expressed by natural killer (NK) and CD8+ T lymphocytes, effector cells that are thought to play a role in host defence against tumors. NK cells have also been shown to regulate normal differentiation of hemopoietic precursor into the myeloid or lymphoid cell lineage. Moreover, it has been stated that NK cells are not able to damage autologous cells, as they receive negative signals through inhibitory receptors, including killer Ig-like receptors (KIR) or C-type lectin inhibitory receptors (CLIR), which bind to HLA-I discrete alleles. Surprisingly, we found that autologous IL2-activated, but not freshly isolated, NK cells lysed MSC, while T lymphocytes did not kill self or non-self MSC. Binding of ICAM-1 expressed by MSC to its receptor, the integrin LFA-1, expressed by NK cells plays a key role in MSC/NK interaction. More importantly, NKG2D/MICA and/or NKG2D/ULBP3 engagement is responsible for the delivery of lethal hit. Conversely, it appears that HLA-I molecules do not protect MSC from NK cell-mediated injury. Taken together, these data suggest that NK cells, when activated as it may occur during the first response to viral infections, are able to eliminate MSC, thus altering the normal interactions with hemopoietic precursors and possibly affecting their differentiation. This mechanism might also contribute to the development of aberrant precursors as observed in acute leukaemias.

Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells

2021 ◽  
Vol 118 (45) ◽  
pp. e2107507118
Author(s):  
Jiao Wang ◽  
Sandra Toregrosa-Allen ◽  
Bennett D. Elzey ◽  
Sagar Utturkar ◽  
Nadia Atallah Lanman ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Specific Activity ◽  
Antibody Fragment ◽  
Genetically Engineered ◽  
Local Concentration ◽  
Local Tumor

Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking, have rendered glioblastoma (GBM) highly resistant to therapy. To address these obstacles, here we describe a unique, sophisticated combinatorial platform for GBM: a cooperative multifunctional immunotherapy based on genetically engineered human natural killer (NK) cells bearing multiple antitumor functions including local tumor responsiveness that addresses key drivers of GBM resistance to therapy: antigen escape, immunometabolic reprogramming of immune responses, and poor immune cell homing. We engineered dual-specific chimeric antigen receptor (CAR) NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site–specific activity in the tissue, and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising NK cell–based combinatorial strategy that can target multiple clinically recognized mechanisms of GBM progression simultaneously.

scholarly journals NK cell upraise in the dark world of cancer stem cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Alireza Shokouhifar ◽  
Javad Firouzi ◽  
Masoumeh Nouri ◽  
Gholamreza Anani Sarab ◽  
Marzieh Ebrahimi
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Advanced Technology ◽  
Cell Based Therapy ◽  
Radio Therapy ◽  
Cancer Types ◽  
Advanced Treatments

AbstractOne of the obstacles in treating different cancers, especially solid tumors, is cancer stem cells (CSCs) with their ability in resistance to chemo/radio therapy. The efforts for finding advanced treatments to overcome these cells have led to the emergence of advanced immune cell-based therapy (AICBT). Today, NK cells have become the center of attention since they have been proved to show an appropriate cytotoxicity against different cancer types as well as the capability of detecting and killing CSCs. Attempts for reaching an off-the-shelf source of NK cells have been made and resulted in the emergence of chimeric antigen receptor natural killer cells (CAR-NK cells). The CAR technology has then been used for generating more cytotoxic and efficient NK cells, which has increased the hope for cancer treatment. Since utilizing this advanced technology to target CSCs have been published in few studies, the present study has focused on discussing the characteristics of CSCs, which are detected and targeted by NK cells, the advantages and restrictions of using CAR-NK cells in CSCs treatment and the probable challenges in this process.

scholarly journals Inhibition of the αv integrin-TGF-β axis improves natural killer cell function against glioblastoma stem cells

2020 ◽  
Author(s):  
Hila Shaim ◽  
Mayra Hernandez Sanabria ◽  
Rafet Basar ◽  
Fang Wang ◽  
May Daher ◽  
...  
Keyword(s):  
Stem Cells ◽  
Nk Cells ◽  
Single Cell ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Contact ◽  
Glioblastoma Stem Cells

ABSTRACTGlioblastoma, the most aggressive brain cancer, often recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. Here, we show that patient-derived GSCs, but not normal astrocytes, are highly sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. In contrast, single cell analysis of autologous, tissue infiltrating NK cells isolated from surgical samples of high-grade glioblastoma patient tumors using mass cytometry and single cell RNA sequencing revealed an abnormal phenotype associated with impaired lytic function compared with peripheral blood NK cells from GBM patients or healthy donors. This immunosuppression was attributed to an integrin-TGF-β mechanism, activated by direct cell-cell contact between GSCs and NK cells. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling, or with TGF-β receptor 2 gene-edited NK cells prevented GSC-induced NK cell dysfunction and tumor growth. Collectively, our findings reveal a novel mechanism of NK cell immune evasion by GSCs and implicate the integrin-TGF-β axis as a useful therapeutic target to eliminate GSCs in this devastating tumor.

scholarly journals Interleukin-15 Receptor α Chain Knockout NOD-SCID mice have reduced numbers of NK cells, develop thymic lymphomas and fail to engraft human hematopoietic cells

2021 ◽  
Author(s):  
Andrea Vecchione ◽  
Grace Nauman ◽  
Mohsen Khosravi Marharlooei ◽  
Nichole Danzl ◽  
Hao-Wei Li ◽  
...  
Keyword(s):  
Nk Cells ◽  
Lymphoid Tissue ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Scid Mice ◽  
Nsg Mice ◽  
Cell Engraftment ◽  
Human T Cell ◽  
Human Immune

AbstractNOD-SCID IL2rγcnull (NSG) mice are widely used to model human immune cell development because they are more permissive for human hematopoietic cell engraftment and reconstitution than NOD-SCID mice. While increased human reconstitution in the blood of NSG mice has been attributed to the absence of mouse NK cells, deletion of the common gamma chain (γc) limits development of lymphoid tissue inducer cells and precludes development of normal secondary lymphoid structures. The disorganized lymphoid tissue leads to compromised human T cell-B cell interactions and results in variable human immune cell function in human immune system (HIS) NSG compared to NOD-SCID mice. We attempted to remove mouse NK cells from NOD-SCID mice while retaining other γc-dependent cytokine responses by targeted disruption of the mouse genomic IL15RA locus with CRISPR/Cas9. IL15Rα is required for the development, function and survival of NK cells. NOD-SCID IL15Rα-/- mice showed reductions in NK cells and NK cell function. However, NOD-SCID IL15Rα-/- mice demonstrated accelerated thymic lymphomagenesis and showed earlier mortality compared to NOD-SCID mice. This result suggests that mouse NK cells are important to delay lymphoma development in NOD-SCID mice. We transplanted thymectomized NOD-SCID ILl5Rα-/- mice with human fetal liver CD34+ cells and thymus to determine if these mice supported engraftment and development of a transplanted HIS. Surprisingly, we found that peripheral human engraftment was inferior (mean 0.05% of lymphocytes) to that in both NOD-SCID (mean, 10.5% of lymphocytes) and NSG (mean, 54% of lymphocytes) mice. These results indicate that NOD-SCID IL15Rα-/- mice are not permissive for human CD34+ cell engraftment.

Modulation of Immune Cell Responses by Human Mesenchymal Stem Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1288-1288 ◽  
Author(s):  
Sudeepta Aggarwal ◽  
Mark F. Pittenger
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Dendritic Cells ◽  
Cell Surface ◽  
Nk Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Human Mscs ◽  
Ifn Γ

Abstract Mesenchymal stem cells (hMSCs) are multipotent stem cells that have the capacity to differentiate into various lineages. These cells provide stromal support and can be utilized as a feeder layer for expansion of hematopoitic stem cells and embryonic stem cells. Furthermore, allo-transplanted MSCs are not rejected and have been shown to mediate immuno-modulatory functions in vitro. Also, MSCs have been found at the wound site at extended times. The mechanisms underlying MSC migration and immuno-modulation are still under investigation. Aim: To understand the factors involved in human MSC (hMSC) migration and their interaction with various immune cell types. Methods: Human MSCs were examined for the presence of cell surface receptors that may play a role in migration using quantitative RT-PCR. Next, hMSCs were co-cultured with purified immune cell types including dendritic cells (DCs), naïve T cells and NK cells. Following the co-culture, changes in the phenotype of the immune cells under activating conditions were analyzed using ELISA and functional assays. Results: Human MSCs express Toll receptors, especially TLR4, on their cell surface. The TLR4 on hMSCs is functional as seen by a several-fold increase in IL-6 and chemokine IL-8 upon incubation with TLR4 exogenous ligand lipopolysaccharide (LPS) and the endogenous ligand, soluble hyaluronic acid (sHA). When hMSCs were incubated with activated dendritic cells, there was a >50% decrease in TNF-α secretion and a >50% increase in IL-10 secretion. When hMSCs were incubated with naïve T cells, hMSCs decreased IFN-γ secretion and increased IL-4 secretion. Decreased IFN-γ was also seen when MSCs were incubated with NK cells. Conclusion: These results suggest that (i) hMSCs may respond to the signals generated by breakdown products of extracellular matrix (e.g. sHA) via TLR4 and assist in wound healing (ii) hMSCs immuno-modulatory effects are mediated by interacting with various immune cell types and altering their phenotypic response to a more tolerant and anti-inflammatory response.

scholarly journals IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

2019 ◽  
Author(s):  
Elia Moreno Cubero ◽  
Stefan Balint ◽  
Aljawharah Alrubayyi ◽  
Ane Ogbe ◽  
Rebecca Matthews ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Nk Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Mammalian Target Of Rapamycin ◽  
Dynamic Regulation ◽  
Cell Responses ◽  
Pre Treatment ◽  
Hiv 1

AbstractDynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly influence immune cell function and differentiation including Natural Killer (NK) cell responses. Persistent HIV-1 infection leads to a state of chronic activation, subset redistribution and progressive NK cell dysregulation. In this study we examined the metabolic processes that characterise NK cell subsets in HIV-1 infection, including adaptive NK cell subpopulations expressing the activating receptor NKG2C, which expand during chronic infection. These adaptive NK cells exhibit an enhanced metabolic profile in human cytomegalovirus (HCMV) infected HIV-1 seronegative individuals. However, the bioenergetic advantage of adaptive CD57+NKG2C+ NK cells is diminished during chronic HIV-1 infection, where NK cells uniformly display reduced oxidative phosphorylation (OXPHOS) and limited fuel flexibility upon CD16 stimulation. Defective OXPHOS was accompanied by increased mitochondrial depolarisation and structural alterations indicative of mitochondrial dysfunction, suggesting that mitochondrial defects are restricting the metabolic plasticity of NK cell subsets in HIV-1 infection. The metabolic requirement for receptor stimulation was alleviated upon IL-15 pre-treatment enhancing mammalian target of rapamycin complex1 (mTORC1) activity and NK cell functionality in HIV-1 infection, representing an effective strategy for pharmacologically boosting NK cell responses.

The Mechanism of the Initiation and Progression of Glioma

2013 ◽  
Vol 80 (5) ◽  
Author(s):  
Ishwar K. Puri ◽  
Subbiah Elankumaran ◽  
Moanaro Biswas ◽  
Liwu Li
Keyword(s):  
Stem Cells ◽  
Nk Cells ◽  
Intracellular Signaling ◽  
Immune Cell ◽  
Nk Cell ◽  
Tumor Regression ◽  
Malignant Gliomas ◽  
Experimental Studies ◽  
Cell Types ◽  
Beneficial Impact

The fate of malignant glioma (MG) is governed by a multifaceted and dynamic circuit that involves the surrounding cellular and molecular tumor microenvironment. Despite extensive experimental studies, a complete understanding of the complex interactions among the constituents of this microenvironment remains elusive. To clarify this, we introduce a biologically based mathematical model that examines the dynamic modulation of glioma cancer stem cells (GSC) by different immune cell types and intracellular signaling pathways. It simulates the proliferation of glioma stem cells due to macrophage-induced inflammation, particularly involving two microglia phenotypes. The model can be used to regulate therapies by monitoring the GSC self-renewal rates that determine tumor progression. We observe that the GSC population is most sensitive to its own proliferation rate and the relative levels of the activating natural killer (NK) cell stimulatory receptors (NKG2D) versus killer inhibitory receptors (KIR) on NK cells that influence the proliferation or demise of the GSC population. Thus, the two most important factors involved in tumorigenesis or tumor regression are (1) GSC proliferation and (2) the functional status of NK cells. Therefore, strategies aimed at blocking proliferation and enhancing NKG2D and KIR signals should have a potentially beneficial impact for treating malignant gliomas.

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