Role of CD137/4-1BB and Its Ligand in the NK Cell Mediated Immune Surveillance of Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 880-880
Author(s):  
Tina Baessler ◽  
Matthias Krusch ◽  
Katrin M. Baltz ◽  
Benjamin J. Schmiedel ◽  
Helga M. Schmetzer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Immune Surveillance ◽  
Cell Reactivity ◽  
Ifn Γ ◽  
Tnfr Superfamily ◽  
Acute Myeloid

Abstract NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance and eradication of hematological malignancies including acute myeloid leukemia (AML). NK cell reactivity is governed by a balance of activating and inhibitory receptors including various members of the TNF receptor (TNFR) superfamily. The TNFR superfamily member CD137/4-1BB has been shown to stimulate proliferation and IFN-γ production, but not cytotoxicity of NK cells in mice. Surprisingly, yet nothing is known regarding the consequences of CD137-CD137 ligand (CD137L) interaction for NK cell reactivity in humans. In this study we demonstrate that CD56dimCD16+ but not CD56brightCD16− NK cells express CD137 upon stimulation with the activating cytokines IL-2 and IL-15 with peak expression between 48 and 60h. Furthermore, we found that 5 of 7 investigated AML cell lines and 16 of 51 (33%) primary AML cells of patients expressed substantial CD137L levels, while no CD137L expression was detected on CD34+ cells of healthy donors (n=5). CD137L expression was not restricted to a specific French-American-British (FAB) subtype, but was significantly (p<0.05, one-way ANOVA) associated with monocytic (FAB M4, M5) differentiation. In addition, no association with a particular cytogenetic abnormality or with expression of MHC class I was observed. Reverse signaling via CD137L into AML cells (n=10) significantly induced the release of the immunoregulatory cytokines IL-10 and TNF (both p<0.05, Mann-Whitney U-test). Surprisingly and in contrast to available data regarding the function of murine CD137, we found that in humans blocking CD137-CD137L interaction caused a significant increase in NK cell cytotoxicity and IFN-γ production about 50% (both p<0.05, Mann-Whitney U-test) in coculture assays with CD137L-expressing patient AML cells and AML cell lines. The inhibitory effect of CD137 on NK cell reactivity was further confirmed in cocultures of NK cells with CD137L-transfectants and by triggering CD137 with an agonistic monoclonal antibody. This indicates that CD137 mediates opposite effects in murine compared to human NK cells. Furthermore we conclude that CD137L expression substantially influences tumor immunoediting by AML cells and diminishes NK cell reactivity against AML.

Role of Glucocorticoid-Induced TNF-Related Protein (GITR) Ligand in the Interaction of Acute Myeloid Leukemia with NK Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 18-18
Author(s):  
Matthias Krusch ◽  
Katrin M. Baltz ◽  
Tina Baessler ◽  
Lothar Kanz ◽  
Helmut R. Salih
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Map Kinases ◽  
Nk Cell ◽  
Immune Surveillance ◽  
Related Protein ◽  
Surface Receptors ◽  
Enhanced Production ◽  
Acute Myeloid

Abstract NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance and eradication of hematological malignancies. The activity of NK cells is governed by a balance of activating and inhibitory surface receptors. Glucocorticoid-induced TNF-related protein (GITR) and its ligand (GITRL) are members of the TNF/TNF receptor (TNFR) superfamily, which mediates multiple cellular functions including proliferation, differentiation, and cell death. Recently we reported that NK cells express GITR while cancer cells express GITRL and GITR-GITRL interaction down regulates NK cell-mediated anti-tumor immunity (Baltz et al., FASEB J 2007). Here we demonstrate that GITRL is expressed on 6 of 7 investigated acute myeloid leukemia (AML) cell lines and on primary AML cells in 30 of 52 (59%) patients, while no GITRL expression was detected on CD34+ cells of healthy donors (n=5). GITRL expression was not restricted to a specific French-American-British (FAB) subtype, but was significantly (p&lt;0.05, one-way ANOVA) associated with monocytic (FAB M4, M5) differentiation. In addition, no association with a particular cytogenetic abnormality or with expression of MHC class I was observed. Reverse signaling via GITRL led to phosphorylation of ERK and JNK resulting in significantly (p&lt;0.05, Mann-Whitney U-test) enhanced production of IL-10 and TNF by patient AML cells (n=10). In line, specific inhibitors for JNK and ERK1/2 blocked the cytokine release by AML cells demonstrating that activation of MAP kinases is responsible for the production of the immunoregulatory cytokines following GITRL stimulation. Importantly, blocking GITR-GITRL interaction in cocultures of AML and NK cells significantly (both &lt;0.05 Mann-Whitney U-test) increased cellular cytotoxicity about 70% and IFN-γ production about 60%, and this was due to restored NK cell NF-κB activity. Thus, GITRL substantially influences immunoediting by AML cells and enables the escape of AML cells from NK cell-mediated immune surveillance. The correlation found between GITRL expression and NK cell susceptibility may provide useful information for NK cell-based immunotherapy.

RANKL Expressed by Acute Myeloid Leukemia Cells Impairs NK Cell-Mediated Immune Surveillance

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2164-2164
Author(s):  
Benjamin J Schmiedel ◽  
Constantin M Wende ◽  
Tina Baessler ◽  
Carolin Scheible ◽  
Stefan Wirths ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Immune Surveillance ◽  
Surface Protein ◽  
Leukemia Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

Abstract Abstract 2164 NK cells play an important role in tumor immunosurveillance, especially of leukemia. Their reactivity is governed by various activating and inhibitory molecules expressed by their targets including multiple members of the TNF family. The TNF family member Receptor Activator of NF-κB ligand (RANKL) and its receptors RANK and osteoprotegerin (OPG) are key regulators of bone remodelling, but recently have also been shown to influence progression of hematopoetic malignancies. Here we studied the yet unkown role of the RANK/RANKL molecule system in NK cells and their reactivity against acute myeloid leukemia (AML). Primary leukemia cells from AML patients were found to substantially express RANKL mRNA and surface protein in 75% of the investigated cases (n=40). Reverse signaling via surface-expressed RANKL into AML blasts induced the release of soluble factors including the immunoregulatory cytokines TNF and IL-10, which impaired NK cell anti-tumor reactivity. Moreover, we observed upregulation of RANK on NK cells among PBMC of healthy donors upon exposure to IL-10. This was not caused by direct effects on NK cells, but was rather due to yet unidentified factors released by monocytes among the PBMC upon IL-10 exposure and could be prevented by the activating cytokine IL-2. Furthermore, functional experiments with NK cells and RANKL transfectants or RANKL-negative controls revealed that forward signaling into RANK-expressing NK cells by tumor-expressed RANKL also directly impaired NK cytotoxicity and IFN-γ production. In line, blocking RANK-RANKL interaction using anti-RANKL antibodies or RANK-Fc fusion protein increased cytotoxicity and cytokine production of allogenic NK cells in cultures with RANKL-positive primary AML cells. Our data indicate that RANKL expression enables immune evasion of leukemia cells both by directly inhibiting reactivity of RANK-expressing NK cells and by orchestrating a reciprocal interplay between AML cells, monocytes and NK cells resulting in an immunosuppressive cytokine milieu. Thus, therapeutic modulation of the RANK/RANKL system, e.g. with Denosumab/AMG162, which is presently being evaluated for treatment of both non-malignant and malignant osteolysis, holds promise to reinforce NK reactivity against hematopoietic malignancies. Disclosures: No relevant conflicts of interest to declare.

Expression of Glucocorticoid-Induced TNF Receptor Ligand on Acute Myeloid Leukemia Cells Mediates the Release of Immunosuppressive Cytokines and Impairs NK Cell-Mediated Immune Surveillance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1941-1941
Author(s):  
Matthias Krusch ◽  
Katrin M. Baltz ◽  
Tina Baessler ◽  
Mercedes Kloss ◽  
Ingrid Kumbier ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Cellular Proliferation ◽  
Nk Cell ◽  
Leukemia Cells ◽  
Tnf Receptor ◽  
Ifn Γ ◽  
Acute Myeloid

Abstract NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance of hematological malignancies including acute myeloid leukemia (AML). Among the molecules influencing host-tumor interaction are many members of the TNF superfamily, which mediate multiple cellular functions including cellular proliferation, differentiation and cell death. The TNF family member Glucocorticoid-induced TNF Receptor (GITR) costimulates effector T cells, modulates apoptosis and nuclear factor kappa B and abrogates suppression of murine but not human regulatory T cells. Its cognate ligand GITRL has been found in various healthy tissues. Recently we reported that NK cells express GITR, while solid tumors express GITR ligand (GITRL), and GITR/GITRL interaction downregulates NK cell cytotoxicity and IFN-γ production. Here we analyzed the role of GITR and its ligand in AML. We report for the first time that GITRL is expressed on primary AML cells in 18 of 30 patients as determined by FACS and RT-PCR analysis. Reverse signaling through GITRL using a recombinant GITR-Ig fusion protein induces the release of the immunoregulatory cytokines IL-10 and TNF as determined by ELISA. GITRL-mediated cytokine production of AML cells is abrogated by inhibition of mitogen activated protein kinase (MAPK) pathways as demonstrated by addition of the specific p38 MAPK inhibitor SB202190, the specific JNK inhibitor SP600125 and the specific ERK Inhibitor II. Furthermore, binding of AML-expressed GITRL to GITR on NK cells downregulates cellular cytotoxicity and IFN-γ production in AML-NK cell cocultures, which can be overcome by addition of GITR-blocking antibodies as determined by cytotoxicity assays and ELISA. Thus, our data indicate that GITRL expression in AML substantially influences tumor immunoediting and enables the escape of leukemia cells from NK cell-mediated immunosurveillance.

The FLT3-Inhibitors Midostaurin, Sunitinib, Sorafenib, and TKI258 Differentially Affect NK Cell-Mediated Immunesurveillance of Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3785-3785
Author(s):  
Julia Salih ◽  
Lothar Kanz ◽  
Helmut R Salih ◽  
Matthias Krusch
Keyword(s):  
Nk Cells ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Immune Surveillance ◽  
Leukemia Cells ◽  
Target Cells ◽  
Cell Reactivity ◽  
Flt3 Inhibitors ◽  
Ifn Γ

Abstract Abstract 3785 Poster Board III-721 FLT3 is a receptor tyrosine kinase with an important role in hematopoietic progenitor cell survival and proliferation. The discovery of internal tandem duplication mutations (ITD) in FLT3 was a major breakthrough in understanding the role of abnormally activated FLT3 in myeloid transformation. Between 15% and 34% of AML patients show FLT3-ITD mutations, and thus the inhibition of FLT3 in combination with chemotherapeutic agents may be a promising stragety in the treatment of Acute Myeloid Leukemia (AML). Several protein kinase inhibitors (PKI) targeting FLT3 like e.g. Midostaurin, Sunitinib, Sorafenib, and TKI258 are currently under preclinical and/or clinical evaluation (http://clinicaltrials.gov/ct2/results?term=AML+and+FLT3). Since those PKI, besides targeting their eponymous enzyme FLT3, also inhibit signaling via other molecules they may impair the effector function of various components of anti-tumor immunity. NK cells as part of the innate immune system play an important role in the immune surveillance of tumors due to their ability to directly kill target cells and to shape adaptive immune responses by secreting cytokines like IFN-γ. Clinical evidence for the particularly important role of NK cells in leukemia has recently been provided by studies of haploidentical stem cell transplantation (Ruggeri et al., Science 2002). We report here that CD107a expression as a surrogate marker for degranulation of NK cells within PBMC is inhibited by pharmacological concentrations of Sorafenib (10μg/ml) and Midostaurin (2μg/ml), but not by Sunitinib (200ng/ml) and TKI258 (125ng/ml). In line, pharmacological concentrations of Sunitinib and TKI258 did not affect NK cell cytotoxicity and IFN-γ production in cocultures with leukemia cells. Sorafenib and Midostaurin caused a clear concentration-dependent inhibition of NK cell cytokine production in response to target cells both in resting and in IL-2 activated state (92% and 66%, respectively at plasma peak levels). Furthermore, pharmacological concentrations of Sorafenib and Midostaurin also reduced lysis of leukemia cells by NK cells (54% and 58%, respectively, E:T ratio 10:1) and thus generally compromised NK cell reactivity. Analysis of NK cell signaling revealed that Sorafenib, but not Midostaurin decreased phosphorylation of PI3K and ERK which are important regulators of NK cell reactivity. Thus, Midostaurin inhibits yet undefined signaling events which are crucial for NK effector functions, but are independent of the “classical” PI3K – Rac – PAK – MEK – ERK pathway and are presently under study. Moreover, in light of the important role of NK cells in the immune surveillance of leukemia and the differential influence of clinically used FLT3-inhibitors on NK cell functions our data indicate that the choice and dosing of the most suitable compound in the treatment of AML requires further characterization and careful consideration. Disclosures: No relevant conflicts of interest to declare.

CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells

Blood ◽  
2010 ◽  
Vol 115 (15) ◽  
pp. 3058-3069 ◽  
Author(s):  
Tina Baessler ◽  
Jean Enno Charton ◽  
Benjamin Joachim Schmiedel ◽  
Frank Grünebach ◽  
Matthias Krusch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Tumor Necrosis Factor Receptor ◽  
Interleukin 10 ◽  
Leukemic Cells ◽  
Monocytic Differentiation ◽  
Cell Reactivity ◽  
Acute Myeloid

Abstract Natural killer (NK) cells play an important role in the immunosurveillance of leukemia. Their reactivity is governed by a balance of activating and inhibitory receptors including various members of the tumor necrosis factor receptor (TNFR) family. Here we report that human NK cells acquire expression of the TNFR family member CD137 upon activation, and NK cells of acute myeloid leukemia (AML) patients display an activated phenotype with substantial CD137 expression. CD137 ligand (CD137L) was detectable on leukemic cells in 35% of 65 investigated AML patients, but not on healthy CD34+ cells, and expression was associated with monocytic differentiation. Bidirectional signaling following CD137-CD137L interaction induced the release of the immunomodulatory cytokines interleukin-10 and TNF by AML cells and directly diminished granule mobilization, cytotoxicity, and interferon-γ production of human NK cells, which was restored by blocking CD137. Cocultures of NK cells with CD137L transfectants confirmed that human CD137 inhibits NK-cell reactivity, while activating signals were transduced by its counterpart on NK cells in mice. Our data underline the necessity to study the function of seemingly analog immunoregulatory molecules in mice compared with men and demonstrate that CD137-CD137L interaction enables immune evasion of AML cells by impairing NK-cell tumor surveillance in humans.

The Role of OX40 and Its Ligand in Acute Myeloid Leukemia: Expression, Function and Modulation of NK Cell Anti-Leukemia Reactivity

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3548-3548
Author(s):  
Carla E Schumacher ◽  
Tina Nuebling ◽  
Martin Hofmann ◽  
Benjamin J Schmiedel ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Clinical Success ◽  
Leukemic Cells ◽  
Cell Reactivity ◽  
Acute Myeloid

Abstract Abstract 3548 The TNF/TNF receptor (TNFR) family comprises various molecules that substantially influence cellular functions of both tumor and immune effector cells. The TNFR family member OX40 has been shown to influence proliferation and differentiation of T cells in autoimmune diseases. Here we studied the yet unknown role of OX40 in acute myeloid leukemia (AML). Substantial surface expression of OX40 was detected on malignant cells of AML patients in 24 of 60 (40%) investigated cases. Expression of OX40 mRNA and protein by leukemic cells was confirmed by analysis of AML cells lines, which displayed substantial surface levels in 6 of 7 investigated cases. Induction of OX40 signaling into AML cells by recombinant OX40L or agonistic antibodies lead to the release of cytokines like IL-10 and TNF which contribute to AML pathophysiology and stimulated metabolic activity (WST test) of the leukemia cells. Moreover, we found that NK cells, which play an important role in anti-tumor immunity and largely contribute to the clinical success of allogeneic stem cell transplantation (SCT) in AML, express OX40 ligand (OX40L) following activation, and OX40L triggering stimulated NK cell reactivity. Functional analyses with OX40 transfectants and OX40-negative controls confirmed that OX40L signaling promotes NK cell cytotoxicity and IFN-γ production. Furthermore, disruption of OX40-OX40L interaction by blocking OX40 F(ab)2 fragments resulted in reduced cytotoxicity and cytokine production of allogenic NK cells, thereby further confirming the stimulatory effect of OX40L on NK cell anti-leukemia reactivity when interacting with its AML-expressed counterpart. Our data suggest that OX40 is involved in disease pathophysiology of AML and identify OX40-OX40L interaction as previously unknown modulator of NK cell immunosurveillance in AML. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals 852 Trifunctional NKp46/CD16a-NK cell engager targeting CD123 overcomes acute myeloid leukemia resistance to ADCC

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A893-A893
Author(s):  
Laurent Gauthier ◽  
Angela Virone-Oddos ◽  
Angela Virone-Oddos ◽  
Jochen Beninga ◽  
Benjamin Rossi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Antitumor Activity ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Ex Vivo ◽  
Activating Receptors ◽  
Acute Myeloid

BackgroundThere is a clear need for targeted therapies to treat acute myeloid leukemia (AML), the most common acute leukemia in adults. CD123 (IL-3 receptor alpha chain) is an attractive target for AML treatment.1 However, cytotoxic antibody targeting CD123 proved insufficiently effective in a combination setting in phase II/III clinical trials.2 T-cell engagers targeting CD123 displayed some clinical efficacy but were often associated with cytokine release syndrome and neurotoxicity.3 Interest in the use of NK cells for therapeutic interventions has increased in recent years, as a potential safer alternative to T cells. Several NK-cell activating receptors, such as CD16a, NKG2D, and the natural cytotoxicity receptors NKp30 and NKp46, can be targeted to induce antitumor immunity. We previously reported the development of trifunctional NK-cell engagers (NKCEs) targeting a tumor antigen on cancer cells and co-engaging NKp46 and CD16a on NK cells.4MethodsWe report here the design, characterization and preclinical development of a novel trifunctional NK cell engager (NKCE) targeting CD123 on AML cells and engaging the activating receptors NKp46 and CD16a on NK cells. The CD123 NKCE therapeutic molecule was engineered with humanized antibodies targeting NKp464 and CD123.5 We compared CD123-NKCE and a cytotoxic ADCC-enhanced antibody (Ab) targeting CD123, in terms of antitumor activity in vitro, ex vivo and in vivo. Pharmacokinetic, pharmacodynamic and safety profile of CD123-NKCE were evaluated in non-human primate (NHP) studies.ResultsThe expression of the high affinity Fc gamma receptor CD64 on patient-derived AML cells inhibited the ADCC of the Ab targeting CD123 in vitro and ex vivo, but not the antitumor activity of CD123-NKCE. CD123-NKCE had potent antitumor activity against primary AML blasts and AML cell lines, promoted strong NK-cell activation and induced cytokine secretion only in the presence of AML target cells. Its antitumor activity in mouse model was greater than that of the comparator antibody. Moreover, CD123-NKCE had strong and prolonged pharmacodynamic effects in NHP when used at very low doses, was well-tolerated up to high 3 mg/kg dose and triggered only minor cytokine release.ConclusionsThe data for activity, safety, pharmacokinetics, and pharmacodynamics provided here demonstrate the superiority of CD123-NKCE over comparator cytotoxic antibody, in terms of antitumor activity in vitro, ex vivo, in vivo, and its favorable safety profile, as compared to T-cell therapies. These results constitute proof-of-principle for the efficacy of CD123-NKCE for controlling AML tumors in vivo, and provide consistent support for their clinical development.ReferencesEhninger A, Kramer M, Rollig C, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J 2014;4:e218.Montesinos P, Gail J Roboz GJ, et al. Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia 2021;35(1):62–74.Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood 2021;137(6):751–762.Gauthier L, Morel A, Anceriz N, et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell 2019;177(7):1701–13.Jin L, Lee EM, Ramshaw HS, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 2009;5:31–42.

scholarly journals Characterization of the DNAM-1, TIGIT and TACTILE Axis on Circulating NK, NKT-Like and T Cell Subsets in Patients with Acute Myeloid Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2171
Author(s):  
Isabel Valhondo ◽  
Fakhri Hassouneh ◽  
Nelson Lopez-Sejas ◽  
Alejandra Pera ◽  
Beatriz Sanchez-Correa ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Healthy Volunteers ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Cell Activation ◽  
Nk Cell ◽  
T Cell Subsets ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) remains a major clinical challenge due to poor overall survival, which is even more dramatic in elderly patients. TIGIT, an inhibitory receptor that interacts with CD155 and CD112 molecules, is considered as a checkpoint in T and NK cell activation. This receptor shares ligands with the co-stimulatory receptor DNAM-1 and with TACTILE. The aim of this work was to analyze the expression of DNAM-1, TIGIT and TACTILE in NK cells and T cell subsets in AML patients. Methods: We have studied 36 patients at the time of diagnosis of AML and 20 healthy volunteers. The expression of DNAM-1, TIGIT and TACTILE in NK cells and T cells, according to the expression of CD3 and CD56, was performed by flow cytometry. Results: NK cells, CD56− T cells and CD56+ T (NKT-like) cells from AML patients presented a reduced expression of DNAM-1 compared with healthy volunteers. An increased expression of TIGIT was observed in mainstream CD56− T cells. No differences were observed in the expression of TACTILE. Simplified presentation of incredibly complex evaluations (SPICE) analysis of the co-expression of DNAM-1, TIGIT and TACTILE showed an increase in NK and T cells lacking DNAM-1 and co-expressing TIGIT and TACTILE. Low percentages of DNAM-1−TIGIT+TACTILE+ NK cells and DNAM-1− TIGIT+TACTILE+ CD56− T cells were associated with a better survival of AML patients. Conclusions: The expression of DNAM-1 is reduced in NK cells and in CD4+ and CD8+ T cells from AML patients compared with those from healthy volunteers. An increased percentage of NK and T cells lacking DNAM-1 and co-expressing TIGIT and TACTILE is associated with patient survival, supporting the role of TIGIT as a novel candidate for checkpoint blockade.

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