scholarly journals Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Marina Gazdic ◽  
Bojana Simovic Markovic ◽  
Nemanja Jovicic ◽  
Maja Misirkic-Marjanovic ◽  
Valentin Djonov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lung Cancer ◽  
Stem Cells ◽  
Immune Response ◽  
Mesenchymal Stem Cells ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Cancer Metastasis ◽  
Antitumor Immune Response ◽  
Lung Cancer Metastasis

Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of metastasis. MSCs significantly augmented lung cancer metastasis, attenuate concentrations of proinflammatory cytokines (TNF-α, IL-17), and increase levels of immunosuppressive IL-10, nitric oxide, and kynurenine in sera of LLC1-treated mice. MSCs profoundly reduced infiltration of macrophages, TNF-α-producing dendritic cells (DCs), TNF-α-, and IL-17-producing CD4+ T cells but increased IL-10-producing CD4+ T lymphocytes in the lungs of tumor-bearing animals. The total number of lung-infiltrated, cytotoxic FasL, perforin-expressing, TNF-α-, and IL-17-producing CD8+ T lymphocytes, and NKG2D-expressing natural killer (NK) cells was significantly reduced in LLC1 + MSC-treated mice. Cytotoxicity of NK cells was suppressed by MSC-conditioned medium. This phenomenon was abrogated by the inhibitors of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO), suggesting the importance of iNOS and IDO for MSC-mediated suppression of antitumor cytotoxicity of NK cells. This study provides the evidence that MSCs promote lung cancer metastasis by suppressing antitumor immune response raising concerns regarding safety of MSC-based therapy in patients who have genetic susceptibility for malignant diseases.

scholarly journals Reciprocal modulation of mesenchymal stem cells and tumor cells promotes lung cancer metastasis

EBioMedicine ◽  
2018 ◽  
Vol 29 ◽  
pp. 128-145 ◽  
Author(s):  
Giulia Fregni ◽  
Mathieu Quinodoz ◽  
Emely Möller ◽  
Joanna Vuille ◽  
Sabine Galland ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Lung Cancer Metastasis

Jinfukang inhibits lung cancer metastasis by upregulating CX3CL1 to recruit NK cells to kill CTCs

2021 ◽  
pp. 114175
Author(s):  
Zu-Jun Que ◽  
Jia-Liang Yao ◽  
Zhi-Yi Zhou ◽  
Pan Yu ◽  
Bin Luo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Nk Cells ◽  
Cancer Metastasis ◽  
Lung Cancer Metastasis

scholarly journals The endometrium as a source of mesenchymal stem cells in domestic animals and possible applications in veterinary medicine

2017 ◽  
Vol 4 (3) ◽  
Author(s):  
Ana G. Serrato López ◽  
Juan J. Montesinos Montesinos ◽  
Santiago R. Anzaldúa Arce
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Veterinary Medicine ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Domestic Animals ◽  
Clinical Tool ◽  
Cellular Contact ◽  
Activated T Lymphocytes

Mesenchymal stem cells (MSCs) have been isolated from the endometrium of humans, mice, cows, pigs and ewes. Typically, these cells are detected in the deep regions of the endometrium, closer to the union with the myometrium. MSCs possess characteristics such as clonogenicity and multipotentiality since they can differentiate in vitro into adipogenic, chondrogenic and osteogenic lineages. These cells can be induced to differentiate in vitro not only into the mesodermal lineage but also into the endodermal and ectodermal lineages. Therefore, MSCs show a great regenerative capacity for various organs and tissues, including the endometrium. Some advantages of endometrial MSCs compared with other MSC sources are their immune modulating activity, their ease of obtainment, and the amount of sample that may be collected. The study of endometrial MSCs in domestic animals is a new and promising field because increasing our understanding of the physiology and biology of these cells may lead to a better understanding of the physiopathology of reproductive diseases, and the development of treatment methods for infertility problems. In other veterinary medicine fields, MSCs can be used for the treatment of autoimmune diseases, cardiac affections, musculoskeletal and articular lesions, muscle degeneration, type 1 diabetes, urinary tract diseases, neurodegenerative processes and tumours. Finally, MSCs are also an important clinical tool for tissue engineering and regenerative medicine. The aim of this review is to present an updated outlook of the knowledge regarding endometrial MSCs and their possible applications in veterinary medicine.Figure 1: Immunoregulatory ability of MSCs. MSCs regulate the functions of NK cells, dendritic cells (DC) and T lymphocytes. The immunosuppressive effect may occur through the secretion of different factors or through cellular contact (black arrows). The former pathway involves TGFß, HGF, IL-10, PGE2, and HLA-G5, whereas the latter pathway involves the products of IDO enzyme activity, PD-L1, HLA-G1, ICAM-I and VCAM-I. Pro-inflammatory cytokines (IFN-?) secreted by NK cells and activated T lymphocytes favour the immunoregulatory activity of MSCs (dotted lines), because they increase or induce the secretion of molecules that regulate the functions of the distinct cellular components of the immune system. Modified from Montesinos et al, and Ma et al.19,66

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

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.

scholarly journals Cancer-educated mesenchymal stem cells promote the survival of cancer cells at primary and distant metastatic sites via the expansion of bone marrow-derived-PMN-MDSCs

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Buqing Sai ◽  
Yafei Dai ◽  
Songqing Fan ◽  
Fan Wang ◽  
Lujuan Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Primary Tumour ◽  
Lung Cancer Cells ◽  
Gm Csf ◽  
Metastatic Sites

AbstractBone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that can differentiate into a variety of cell types. BMSCs are chemotactically guided towards the cancer cells and contribute to the formation of a cancer microenvironment. The homing of BMSCs was affected by various factors. Disseminated tumour cells (DTCs) in distant organs, especially in the bone marrow, are the source of cancer metastasis and cancer relapse. DTC survival is also determined by the microenvironment. Here we aim to elucidate how cancer-educated BMSCs promote the survival of cancer cells at primary tumour sites and distant sites. We highlight the dynamic change by identifying different gene expression signatures in intratumoral BMSCs and in BMSCs that move back in the bone marrow. Intratumoral BMSCs acquire high mobility and displayed immunosuppressive effects. Intratumoral BMSCs that ultimately home to the bone marrow exhibit a strong immunosuppressive function. Cancer-educated BMSCs promote the survival of lung cancer cells via expansion of MDSCs in bone marrow, primary tumour sites and metastatic sites. These Ly6G+ MDSCs suppress proliferation of T cells. CXCL5, nitric oxide and GM-CSF produced by cancer-educated BMSCs contribute to the formation of malignant microenvironments. Treatment with CXCL5 antibody, the iNOS inhibitor 1400w and GM-CSF antibody reduced MDSC expansion in the bone marrow, primary tumour sites and metastatic sites, and promoted the efficiency of PD-L1 antibody. Our study reveals that cancer-educated BMSCs are the component of the niche for primary lung cancer cells and DTCs, and that they can be the target for immunotherapy.

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.

scholarly journals Deprivation of human natural killer cells and antitumor immune response

2014 ◽  
Vol 2 ◽  
Author(s):  
Vyacheslav Ogay ◽  
Aliya Sekenova ◽  
Inpyo Choi
Keyword(s):  
Stem Cells ◽  
Immune Response ◽  
Nk Cells ◽  
Induced Pluripotent Stem Cells ◽  
Natural Killer ◽  
Pluripotent Stem Cells ◽  
Antitumor Immune Response ◽  
Efficient Treatment ◽  
Cd34 Cells ◽  
Induced Pluripotent

Introduction: Cell-based immunotherapy has been given increased attention as a treatment for cancer. Human natural killer (NK) cells are resident lymphocyte populations. They exhibit potent antitumor activity without human leukocyte antigen matching and without prior antigen exposure. They also are a promising tool for immunotherapy of solid and hematologic cancers. However, most cancer patients do not have enough NK cells to induce an effective antitumor immune response. This demonstrates a need for a source of NK cells that can supplement the endogenous cell population.Material and methods: In this study, we derived induced pluripotent stem cells (iPSCs) from peripheral blood T-lymphocytes using Sendai virus vectors.Results: Generated iPSCs exhibited monoclonal T cell receptors (TCR) rearrangement in their genome, a hallmark of mature terminally differentiated T cells. These iPSCs were differentiated into NK cells using a two-stage coculture system: iPSCs into hematopoietic CD34+ cells with feeder cells M210-B4 (ATCC, USA) and CD34+ cells into mature NK cells with AFT024 cells (ATCC, USA). Our results showed that iPSC-derived NK cells expressed CD56, CD16, NKp 44 and NKp 46, possessed high cytotoxic activity  and produced high level of interferon-γ.Conclusion: Based on our data, derivation of NK cells from induced pluripotent stem cells should be considered in the treatment of oncologic diseases.This would allow for the development of cell therapy for cancer using immunologically compatible NK cells derived from iPSCs. This may contribute to a more efficient treatment of oncologic diseases in addition to traditional cancer treatment.

LIGHT Delivery to Tumors by Mesenchymal Stem Cells Mobilizes an Effective Antitumor Immune Response

2012 ◽  
Vol 72 (12) ◽  
pp. 2980-2989 ◽  
Author(s):  
Weibin Zou ◽  
Huilin Zheng ◽  
Tong-Chuan He ◽  
Jinjia Chang ◽  
Yang-Xin Fu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Immune Response ◽  
Mesenchymal Stem Cells ◽  
Antitumor Immune Response ◽  
Light Delivery ◽  
Effective Antitumor Immune Response
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