scholarly journals Favorable in vitro effects of combined IL-12 and IL-18 treatment on NK cell cytotoxicity and CD25 receptor expression in metastatic melanoma patients

2015 ◽  
Vol 13 (1) ◽  
Author(s):  
Katarina Mirjačić Martinović ◽  
Nada Babović ◽  
Radan Džodić ◽  
Vladimir Jurišić ◽  
Suzana Matković ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Nk Cell ◽  
Receptor Expression ◽  
Cell Cytotoxicity ◽  
Melanoma Patients ◽  
Nk Cell Cytotoxicity ◽  
In Vitro Effects

Low expression of CD161 and NKG2D activating NK receptor is associated with impaired NK cell cytotoxicity in metastatic melanoma patients

2007 ◽  
Vol 24 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Gordana Konjević ◽  
Katarina Mirjačić Martinović ◽  
Ana Vuletić ◽  
Viktor Jović ◽  
Vladimir Jurisić ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Nk Cell ◽  
Cell Cytotoxicity ◽  
Melanoma Patients ◽  
Nk Cell Cytotoxicity ◽  
Nk Receptor ◽  
Low Expression

scholarly journals Enhancing NK cell-mediated cytotoxicity to cisplatin-resistant lung cancer cells via MEK/Erk signaling inhibition

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Li Yang ◽  
MingJing Shen ◽  
Li Jun Xu ◽  
Xiaodong Yang ◽  
Ying Tsai ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Death Receptor ◽  
Neutralizing Antibody ◽  
Erk Signaling ◽  
Cytotoxic Action ◽  
Cell Cytotoxicity ◽  
Nk Cell Cytotoxicity ◽  
Resistant Cells

Abstract Major progress has been made clinically in inhibiting the programmed death receptor 1 (PD-1)/PD-L1 interaction to enhance T cell-mediated immune function, yet the effectiveness of anti-PD-L1/PD-1 agents in enhancing natural killer (NK) cell’s function remains largely unknown. Susceptibilities of cisplatin-resistant A549CisR and H157CisR cells vs. parental cells to the cytotoxic action of NK cells were examined. We found cisplatin-resistant cells more resistant to NK cell cytotoxicity than parental cells. There were constitutively higher expressions of PD-L1 in A549CisR and H157CisR cells than in parental cells in vitro, as well as in H157CisR cell-derived tumors than H157P cell-derived tumors. In contrast, we observed that the expression of PD-1 in NK cells was induced after co-culture with cisplatin-resistant cells. We also observed increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity when neutralizing antibody of PD-1 or PD-L1 was added. Further, we found that the NK group 2, member D (NKG2D) ligand levels were lower in A549CisR and H157CisR cells than in parental cells. Meanwhile, we discovered that the MEK/Erk signaling pathway played a significant role in this regulation, and the addition of a MEK/Erk pathway inhibitor significantly enhanced the PD-L1 Ab effect in enhancing NK cell cytotoxicity to cisplatin-resistant cells.

In Vitro and In Vivo Sensitization of Malignant Cells to Autologous Natural Killer Cell Cytotoxicity Following Exposure to Bortezomib.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 925-925 ◽  
Author(s):  
Andreas Lundqvist ◽  
Kristy Greeneltch ◽  
Maria Berg ◽  
Shivani Srivastava ◽  
Nanae Harashima ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Cell Cytotoxicity ◽  
Malignant Cells ◽  
Nk Cell Cytotoxicity ◽  
Tumor Death

Abstract Killer IgG like receptor (KIR) inactivation of NK cells by self HLA molecules has been proposed as a mechanism through which malignant cells evade host NK cell-mediated immunity. To overcome this limitation, we sought to develop a method to sensitize the patient’s tumor to autologous NK cell cytotoxicity. The proteasome inhibitor bortezomib has recently been shown to enhance the activity of tumor death receptors. We found that exposure of a variety of different leukemia, lymphoma and solid tumor cancer cell lines to sub-apoptotic doses of bortezomib sensitized tumor cells in vitro to lysis by allogeneic NK cells. Importantly, this sensitizing effect also occurs with autologous NK cells normally rendered inactive via tumor KIR ligands; NK cells expanded from patients with metastatic renal cell carcinoma were significantly more cytotoxic against the patient’s own autologous tumor cells when pretreated with bortezomib compared to untreated tumors. This sensitization to autologous NK cell killing was also observed in vivo in two different murine tumor models. A significant delay in tumor growth in C57BL/6 mice bearing LLC1 tumors (figure) and a delay in tumor growth and a significant prolongation (p<0.01) in survival were observed in RENCA tumor bearing Balb/c mice treated with bortezomib and syngeneic NK cell infusions compared to untreated mice or animals treated with bortezomib alone or NK cells alone. An investigation into the mechanism through which NK cell cytotoxicity was potentiated revealed bortezomib enhanced the activity of tumor death receptor-dependent and -independent apoptotic pathways. More specifically, bortezomib sensitized human and murine tumor cells to TRAIL and perforin/granzyme mediated NK cell cytotoxicity respectively. These observations suggest that pretreatment of malignant cells with bortezomib could be used as a strategy to override NK cell inhibition via tumor KIR ligands, thus potentiating the activity of adoptively infused autologous NK cells. A clinical trial evaluating the safety and anti-tumor efficacy of adoptively infused autologous NK cells in patients with advanced malignancies with and without tumor sensitization using bortezomib is currently being explored. Figure: Tumor growth in LLC1 bearing C57BL/6 mice. Fourteen days following s.c. injection of 3x105 LLC1 tumor cells, mice received 15μg (i.p) bortezomib and/or an adoptive infusion of 1x106 NK cells from C57BL/6 mice (i.v) given on day 15. Each dot represents the tumor volume of individual mice measured on day 28 post tumor injection. Tumors were significantly smaller in mice treated with bortezomib followed by NK cells compared to controls or mice that received either NK cells alone or bortezomib alone (p<0.04 for all groups). Figure:. Tumor growth in LLC1 bearing C57BL/6 mice. . / Fourteen days following s.c. injection of 3x105 LLC1 tumor cells, mice received 15μg (i.p) bortezomib and/or an adoptive infusion of 1x106 NK cells from C57BL/6 mice (i.v) given on day 15. Each dot represents the tumor volume of individual mice measured on day 28 post tumor injection. Tumors were significantly smaller in mice treated with bortezomib followed by NK cells compared to controls or mice that received either NK cells alone or bortezomib alone (p<0.04 for all groups).

Polysaccharide enhanced NK cell cytotoxicity against pancreatic cancer via TLR4/MAPKs/NF-κB pathway in vitro/vivo

2019 ◽  
Vol 225 ◽  
pp. 115223 ◽  
Author(s):  
Xin Xie ◽  
Lingman Ma ◽  
Yiran Zhou ◽  
Wen Shen ◽  
Duiyue Xu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Nk Cell ◽  
Cell Cytotoxicity ◽  
Nk Cell Cytotoxicity

Tim-3 expression and function in natural killer cells from advanced melanoma patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8571-8571
Author(s):  
Ines Esteves Domingues Pires Da Silva ◽  
Sonia Jimenez-Baranda ◽  
Anne Gallois ◽  
Vijay Kuchroo ◽  
Iman Osman ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Advanced Melanoma ◽  
Target Cells ◽  
Cell Cytotoxicity ◽  
Healthy Donors ◽  
Melanoma Patients ◽  
Ifn Γ ◽  
Nk Cell Cytotoxicity ◽  
And Function

8571 Background: The concept of CD8+ T cell exhaustion in the context of metastatic cancer has been reinforced by the recent success of immunotherapies targeting the exhaustion markers CTLA-4 and PD-1 in advanced melanoma. T-cell immunoglobulin 3 (Tim-3), another exhaustion marker, is also expressed in natural killer (NK) cells, however its role is still unknown. Recent reports have shown that NK cells, innate immune cells that eliminate tumors through cytotoxicity and IFN-g production, are functionally impaired in advanced melanoma patients, although no receptor has been linked with that phenotype so far. In this study, we characterize the role of Tim-3 in NK cells, particularly in the presence of its natural ligand, Galectin-9 (Gal-9), that is known to be expressed/secreted by some tumor cells including melanoma. Methods: We compared 20 advanced melanoma donors NK cells with 40 healthy donors NK cells as it relates to Tim-3 expression (by flow cytometry) and function (cytotoxicity, IFN-γ production and proliferation). NK cells cytotoxicity was measured by lamp-1 expression, and two different target cells were used: i) K562 cells (Gal-9-) and ii) Gmel Gal-9+ and Gmel Gal-9- sorted melanoma cells. Proliferation was quantified by CFSE after 6 days in the presence of rhIL-2. Recombinant rhGal9 effect was tested in cytotoxicity and IFN-γ production. Results: Melanoma patients NK cells express higher levels of Tim-3 compared to healthy donors NK cells (p<0.05). Melanoma patients NK cells have a defect in cytotoxicity, proliferation and IFN-γ production. Tim-3 expression by itself (without engagement of specific ligands) does not negatively affect NK cell functions (p<0.05). However, when rhGal9 is added to the system, a decrease in NK cell cytotoxicity and IFN-γ production (p<0.05) was observed. Finally, the expression of Gal-9 by the target cells induces a defect in NK cell cytotoxicity (Gmel Gal-9+ vs Gmel Gal-9-). Conclusions: These data suggest that advanced melanoma patients NK cells are exhausted, although it still remains unclear if Tim-3 is involved in this phenotype. In addition,the expression/secretion of Galectin-9, immunosuppressive for NK cells, may be a possible mechanism for tumors to evade immune surveillance.

Tumor-Derived Microvesicles From Sera of Patients with Acute Myeloid Leukemia Suppresses NK Cell Cytotoxicity Via Transforming Growth Factor Beta-1.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2678-2678
Author(s):  
Miroslaw J Szczepanski ◽  
Marta E Szajnik ◽  
Malgorzata Czystowska ◽  
Magis Mandapathil ◽  
Ann Welsh ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Receptor Expression ◽  
Cell Cytotoxicity ◽  
Western Blots ◽  
Cell Suppression ◽  
Nk Cell Cytotoxicity ◽  
Acute Myeloid

Abstract Abstract 2678 Poster Board II-654 Natural killer (NK) cell cytotoxicity in patients with acute myeloid leukemia (AML) is significantly decreased relative to that in normal controls (NC). However, the mechanisms responsible for low NK cell activity in AML are not known. We considered the possibility that tumor-cell-derived microvesicles (MV) mediate suppression of NK cells. MV originate from the endosomal compartment of activated normal and neoplastic cells. Evidence suggests that tumor-derived MV exert detrimental effects on cells of the immune system and may play a role in tumor progression. To determine their contribution to immune suppression in AML, MV were isolated from sera of patients newly diagnosed with AML prior to any treatment and used to evaluate MV-mediated NK cell suppression. The protein content of MV isolated using exclusion chromatography and ultracentrifugation from sera of 19 AML patients was significantly higher than that of MV isolated from sera of 25 NC (75μg±12/mL vs 1.2μg±0.4/mL, p<0.001 ). MV from AML patients were positive for membrane-associated TGFb-1 and FasL in Western blots, whereas no TGFb-1 or FasL was detected in MV from NC. For functional assays, NK cells sorted from peripheral blood of NC were cultured with MV isolated from sera of the AML patients. A significant decrease in NK cell cytotoxicity was observed after co-incubation with MV (2412 LU before vs 1640 LU after, p<0.002). Concomitantly, a decrease in the expression of the NK cell activating receptor, NKG2D, was observed (57% before vs 38% after, p<0.001). The addition of TGFb1-neutralizing antibody abrogated the effects of MV on the NK cell cytotoxicity and receptor expression. The increased levels in sera of AML patients of MV mediating potent NK cell suppression is likely to compromise anti-tumor immune responses. Therefore, modulation of the levels and functions of MV might provide new immunotherapeutic approaches in AML. Disclosures: No relevant conflicts of interest to declare.

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