scholarly journals Impact of NK Cell Activating Receptor Gene Variants on Receptor Expression and Outcome of Immunotherapy in Acute Myeloid Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Brwa Ali Hussein ◽  
Alexander Hallner ◽  
Lovisa Wennström ◽  
Mats Brune ◽  
Anna Martner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Receptor Gene ◽  
Receptor Expression ◽  
Gene Variants ◽  
Nk Cell Receptors ◽  
Activating Receptor ◽  
Acute Myeloid

Natural killer cells are important effector cells in the immune response against myeloid malignancies. Previous studies show that the expression of activating NK cell receptors is pivotal for efficient recognition of blasts from patients with acute myeloid leukemia (AML) and that high expression levels impact favorably on patient survival. This study investigated the potential impact of activating receptor gene variants on NK cell receptor expression and survival in a cohort of AML patients receiving relapse-preventive immunotherapy with histamine dihydrochloride and low-dose IL-2 (HDC/IL-2). Patients harboring the G allele of rs1049174 in the KLRK1 gene encoding NKG2D showed high expression of NKG2D by CD56bright NK cells and a favorable clinical outcome in terms of overall survival. For DNAM-1, high therapy-induced receptor expression entailed improved survival, while patients with high DNAM-1 expression before immunotherapy associated with unfavorable clinical outcome. The previously reported SNPs in NCR3 encoding NKp30, which purportedly influence mRNA splicing into isoforms with discrete functions, did not affect outcome in this study. Our results imply that variations in genes encoding activating NK cell receptors determine receptor expression and clinical outcome in AML immunotherapy.

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.

scholarly journals Phenotypic and functional changes of NK cells in patients with myelodysplastic syndrome and acute myeloid leukemia treated with hypomethylating drugs

2021 ◽  
Vol 23 (2) ◽  
pp. 223-230
Author(s):  
D. I. Zhigarev ◽  
M. V. Khoreva ◽  
L. V. Gankovskaya
Keyword(s):  
Immune Response ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Nk Cells ◽  
Critical Analysis ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Receptor Expression ◽  
Functional Characteristics ◽  
Acute Myeloid

Natural killer cells (NK cells) are cytotoxic lymphocytes that play a pivotal role in maintaining immunological surveillance and in developing an innate immune response. Since the discovery of NK cells in 1973, the mechanisms of their functioning have been studied in details, and there is currently no doubt that they play a special role in the process of recognition and destruction of transformed and malignant cells. Understanding the role of NK cells in antitumor immunity, on the one hand, leads to emergence of new immunotherapeutic strategies and, on the other hand, allows to adjust the existing treatment regimens for tumor diseases, in accordance with the principle of primum non nocere. Optimization of cancer therapy protocols executed in order to protect immune cells from death and functional impairment is an important problem that cannot be successfully resolved without regular aggregation of the results from disparate studies and critical analysis of the all accumulated data.The objective of this review is to create a relevant and holistic picture of changes in the phenotypic and functional characteristics of NK cells in patients with two related hematological diseases – myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). For the treatment of both illnesses, drugs from the group of hypomethylating agents are used, the acting mechanism of which, unlike classical cytostatic agents, is based on modulation of the tumor cell genes expression. All the cells of the body are being affected, including NK cells, since these drugs act nonspecifically. Such an interaction leads to a hypomethylation of NK cell DNA and changes the expression of functional receptors, which, in turn, provide the development of antitumor NK cell immune response.Of course, just the fact of changing gene expression in certain cells does not allow us to fully judge the drug’s impact on the state of immune system. Meanwhile, the origin of this change and its role are important in the context of the disease pathogenesis. Ultimately, a simple description of an increase or decrease in a single receptor expression is not illustrative, since it can lead to uncertain consequences. For this reason, the current review, in addition to describing the existing data on the changes of NK cell receptors expression under the influence of hypomethylating drugs, gives a special attention to critical analysis of functional characteristics of NK cells, including their cytotoxic activity aimed at malignant blast cells, being a determinant of clinical course in the described diseases. 

A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission

Blood ◽  
2012 ◽  
Vol 120 (22) ◽  
pp. 4317-4323 ◽  
Author(s):  
Norbert Vey ◽  
Jean-Henri Bourhis ◽  
Nicolas Boissel ◽  
Dominique Bordessoule ◽  
Thomas Prebet ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Phase 1 ◽  
Receptor Expression ◽  
Clear Correlation ◽  
Hematologic Toxicity ◽  
The European Union ◽  
Acute Myeloid

Abstract IPH2101 is an anti-killer inhibitory receptor (anti-KIR) mAb that can block KIR-mediated inhibition of natural killer (NK) cells to enhance cytotoxicity against acute myeloid leukemia blasts. We have conducted a phase 1 study of IPH2101 in elderly patients with acute myeloid leukemia in first complete remission. Patients received escalating doses (0.0003-3 mg/kg) of IPH2101 following a 3 + 3 design. Safety, toxicity (primary end points), pharmacokinetics, outcome, and immunologic correlates were evaluated. Twenty-three patients (median age, 71 years), were enrolled. Adverse events were mild and transient, consisting mainly of infusion syndrome and erythema. The maximum tolerated dose was not reached, although full KIR saturation (> 90%) was sustained for more than 2 weeks at 1 and 3 mg/kg. There was a clear correlation between mAb exposure and KIR occupancy. Neither hematologic toxicity nor significant changes in the numbers and distribution of lymphocyte subsets, NK cell receptor expression, or in vitro cytotoxicity were seen. At the highest dose levels (0.3, 1, and 3 mg/kg), transient increases in TNF-α and MIP-1β serum concentrations and NK cell CD69 expression were observed. Overall and relapse-free survival in the present study compared favorably to reports in comparable patient populations. We conclude that IPH2101 administration is safe and can block KIR for prolonged periods of time with limited side effects. Registered with the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) as 2005-005298-31.

INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia

Leukemia ◽  
2015 ◽  
Vol 29 (7) ◽  
pp. 1485-1495 ◽  
Author(s):  
I Dzneladze ◽  
R He ◽  
J F Woolley ◽  
M H Son ◽  
M H Sharobim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Therapy Resistance ◽  
Poor Clinical Outcome ◽  
Acute Myeloid

scholarly journals PVRIG is a novel NK cell immune checkpoint receptor in acute myeloid leukemia

Haematologica ◽  
2020 ◽  
pp. 0-0
Author(s):  
Jessica Li ◽  
Sarah Whelan ◽  
Maya F. Kotturi ◽  
Deborah Meyran ◽  
Criselle D’Souza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Surface ◽  
Nk Cells ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Cell Activation ◽  
Nk Cell ◽  
Blocking Antibody ◽  
Poliovirus Receptor ◽  
Acute Myeloid

This study explored the novel immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced NK cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK cell PVRIG expression levels were not increased. To understand how PVRIG blockade might potentially be exploited therapeutically, we investigated the biology of PVRIG and revealed that NK cell activation resulted in reduced PVRIG expression on the cell surface. This occurred whether NK cells were activated by tumour cell recognition, cytokines (IL-2 and IL-12) or activating receptor stimulation (CD16 and NKp46). PVRIG was present at higher levels in the cytoplasm than on the cell surface, particularly on CD56bright NK cells, which further increased cytoplasmic PVRIG levels following IL-2 and IL-12 activation. PVRIG was continually transported to the cell surface via the endoplasmic reticulum (ER) and Golgi in both unstimulated and activated NK cells. Taken together, our findings suggest that anti- PVRIG blocking antibody functions by binding to surface-bound PVRIG, which undergoes rapid turnover in both unstimulated and activated NK cells. We conclude that the PVRIGPVRL2 immune checkpoint axis can feasibly be targeted with PVRIG blocking antibody for NK-mediated immunotherapy of PVRL2+ AML.

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