scholarly journals PTEN regulates natural killer cell trafficking in vivo

2015 ◽  
Vol 112 (7) ◽  
pp. E700-E709 ◽  
Author(s):  
Jeffrey W. Leong ◽  
Stephanie E. Schneider ◽  
Ryan P. Sullivan ◽  
Bijal A. Parikh ◽  
Bryan A. Anthony ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Cell Biology ◽  
Nk Cell ◽  
Killer Cell ◽  
Negative Regulator ◽  
Peripheral Organs

Phosphatase and tensin homolog (PTEN) is a critical negative regulator of the phosphoinositide-3 kinase pathway, members of which play integral roles in natural killer (NK) cell development and function. However, the functions of PTEN in NK cell biology remain unknown. Here, we used an NK cell-specific PTEN-deletion mouse model to define the ramifications of intrinsic NK cell PTEN loss in vivo. In these mice, there was a significant defect in NK cell numbers in the bone marrow and peripheral organs despite increased proliferation and intact peripheral NK cell maturation. Unexpectedly, we observed a significant expansion of peripheral blood NK cells and the premature egress of NK cells from the bone marrow. The altered trafficking of NK cells from peripheral organs into the blood was due to selective hyperresponsiveness to the blood localizing chemokine S1P. To address the importance of this trafficking defect to NK cell immune responses, we investigated the ability of PTEN-deficient NK cells to traffic to a site of tumor challenge. PTEN-deficient NK cells were defective at migrating to distal tumor sites but were more effective at clearing tumors actively introduced into the peripheral blood. Collectively, these data identify PTEN as an essential regulator of NK cell localization in vivo during both homeostasis and malignancy.

scholarly journals In Vivo Monitoring of Natural Killer Cell Trafficking during Tumor Immunotherapy

2014 ◽  
Vol 7 ◽  
pp. MRI.S13145 ◽  
Author(s):  
Naomi S. Sta Maria ◽  
Samuel R. Barnes ◽  
Russell E. Jacobs
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Trafficking ◽  
Cancer Immunotherapies ◽  
Crucial Part

Natural killer (NK) cells are a crucial part of the innate immune system and play critical roles in host anti-viral, anti-microbial, and anti-tumor responses. The elucidation of NK cell biology and their therapeutic use are actively being pursued with 200 clinical trials currently underway. In this review, we outline the role of NK cells in cancer immunotherapies and summarize current noninvasive imaging technologies used to track NK cells in vivo to investigate mechanisms of action, develop new therapies, and evaluate efficacy of adoptive transfer.

Synergistic effects of in vivo depletion of Ly-49A and Ly-49G2 natural killer cell subsets in the rejection of H2b bone marrow cell allografts

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3840-3844 ◽  
Author(s):  
Arati Raziuddin ◽  
Michael Bennett ◽  
Robin Winkler-Pickett ◽  
John R. Ortaldo ◽  
Dan L. Longo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Bone Marrow Cell ◽  
Nk Cell ◽  
Synergistic Effects ◽  
Marrow Cell ◽  
Killer Cell ◽  
F1 Hybrids

Subsets of murine natural killer (NK) cells exist that express the Ly-49 family of molecules that recognize different major histocompatibility complex (MHC) determinants. Bone marrow transplantation studies were performed to examine the in vivo functions of 2 of these subsets. Subsets of Ly-49A and Ly-49G2 NK share specificity for the same MHC class 1 ligand, Dd, binding of which results in an inhibitory signal to the NK cell but allows them to lyse H2b targets in vitro. We therefore examined the ability of these subsets to reject H2b bone marrow cell allografts in lethally irradiated mice. Surprisingly, depletion of Ly-49A+ NK cells in BALB/c or B10.D2 mice (both H2d) had no effect on the rejection of H2b BMC. However, Ly-49A depletion did partially abrogate the ability of B10.BR (H2k) mice to reject H2ballografts. Although depletion of either Ly-49A+ or Ly-49G2+ NK cells alone had no effect on the ability of B10.D2 mice to reject H2b BMC, depletion of both subsets dramatically and synergistically abrogated rejection. Studies with various B10 congenic mice and their F1 hybrids indicate that this synergy between Ly49A and Ly4G2 depletion occurs in every instance. Thus, Ly-49A+ NK cells appear to play a role in the rejection H2b bone marrow allografts, but, in most strains of mice studied, Ly-49G2+ NK cells must also be eliminated. The putative roles of these NK cell subsets in clinical transplantation remains to be elucidated.

Synergistic effects of in vivo depletion of Ly-49A and Ly-49G2 natural killer cell subsets in the rejection of H2b bone marrow cell allografts

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3840-3844 ◽  
Author(s):  
Arati Raziuddin ◽  
Michael Bennett ◽  
Robin Winkler-Pickett ◽  
John R. Ortaldo ◽  
Dan L. Longo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Bone Marrow Cell ◽  
Nk Cell ◽  
Synergistic Effects ◽  
Marrow Cell ◽  
Killer Cell ◽  
F1 Hybrids

Abstract Subsets of murine natural killer (NK) cells exist that express the Ly-49 family of molecules that recognize different major histocompatibility complex (MHC) determinants. Bone marrow transplantation studies were performed to examine the in vivo functions of 2 of these subsets. Subsets of Ly-49A and Ly-49G2 NK share specificity for the same MHC class 1 ligand, Dd, binding of which results in an inhibitory signal to the NK cell but allows them to lyse H2b targets in vitro. We therefore examined the ability of these subsets to reject H2b bone marrow cell allografts in lethally irradiated mice. Surprisingly, depletion of Ly-49A+ NK cells in BALB/c or B10.D2 mice (both H2d) had no effect on the rejection of H2b BMC. However, Ly-49A depletion did partially abrogate the ability of B10.BR (H2k) mice to reject H2ballografts. Although depletion of either Ly-49A+ or Ly-49G2+ NK cells alone had no effect on the ability of B10.D2 mice to reject H2b BMC, depletion of both subsets dramatically and synergistically abrogated rejection. Studies with various B10 congenic mice and their F1 hybrids indicate that this synergy between Ly49A and Ly4G2 depletion occurs in every instance. Thus, Ly-49A+ NK cells appear to play a role in the rejection H2b bone marrow allografts, but, in most strains of mice studied, Ly-49G2+ NK cells must also be eliminated. The putative roles of these NK cell subsets in clinical transplantation remains to be elucidated.

scholarly journals The Potential for Cancer Immunotherapy in Targeting Surgery-Induced Natural Killer Cell Dysfunction

Cancers ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 2 ◽  
Author(s):  
Marisa Market ◽  
Katherine Baxter ◽  
Leonard Angka ◽  
Michael Kennedy ◽  
Rebecca Auer
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Clonal Selection ◽  
Killer Cell ◽  
Cancer Recurrence ◽  
Effector Functions ◽  
Cell Dysfunction ◽  
Cell Functions

Natural Killer (NK) cells are granular lymphocytes of the innate immune system that are able to recognize and kill tumor cells without undergoing clonal selection. Discovered over 40 years ago, they have since been recognized to possess both cytotoxic and cytokine-producing effector functions. Following trauma, NK cells are suppressed and their effector functions are impaired. This is especially important for cancer patients undergoing the removal of solid tumors, as surgery has shown to contribute to the development of metastasis and cancer recurrence postoperatively. We have recently shown that NK cells are critical mediators in the formation of metastasis after surgery. While research into the mechanism(s) responsible for NK cell dysfunction is ongoing, knowledge of these mechanisms will pave the way for perioperative therapeutics with the potential to improve cancer outcomes by reversing NK cell dysfunction. This review will discuss mechanisms of suppression in the postoperative environment, including hypercoagulability, suppressive soluble factors, the expansion of suppressive cell populations, and how this affects NK cell biology, including modulation of cell surface receptors, the potential for anergy, and immunosuppressive NK cell functions. This review will also outline potential immunotherapies to reverse postoperative NK dysfunction, with the goal of preventing surgery-induced metastasis.

scholarly journals Production of colony-stimulating activity by human natural killer cells: analysis of the conditions that influence the release and detection of colony-stimulating activity

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 156-164
Author(s):  
V Pistoia ◽  
S Zupo ◽  
A Corcione ◽  
S Roncella ◽  
L Matera ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Nk Cell ◽  
K562 Cells ◽  
Cell Suspensions ◽  
Normal Peripheral Blood ◽  
Colony Stimulating Activity ◽  
Culture Supernatants

Highly purified natural killer (NK) cell suspensions were tested for their capacity to release colony-stimulating activity (CSA) in vitro. NK cell suspensions comprised primarily CD16+ cells and were devoid of CD3+ T cells, CD15+ monocytes, and of B cells. CSA was detected in the NK cell supernatants and sustained the growth of myeloid colonies from both normal peripheral blood and bone marrow. CSA could be in part inhibited by pretreating NK cell culture supernatants with a specific goat anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antiserum. The inhibition, however, was never complete, a finding that suggests that additional factors were responsible for CSA. Incubation of NK cells with K562 cells (an NK-sensitive target) or with normal bone marrow cells resulted in the appearance of a strong colony- inhibiting activity (CIA) in the culture supernatants. Such CIA was demonstrable in an experimental system where bone marrow or peripheral blood progenitors were induced to form myeloid colonies in the presence of conditioned medium by CSA-producing giant cell tumor (GCT) cells. Stimulation of NK cells with NK-insensitive targets failed to induce CIA production. Neutralizing antitumor necrosis factor (TNF) monoclonal antibodies (MoAbs) were found capable of inhibiting CIA present in the supernatants of NK cells stimulated with K562 cells. Following treatment with anti-TNF antibodies, CSA was again detectable in the same supernatants. This finding indicates that induction of TNF production did not concomitantly switch off CSA production by NK cells. Pretreatment of NK cells with recombinant interleukin-2 (rIL-2) or gamma interferon (r gamma IFN) did not change the amount of CSA released. However, treatment with rIL-2 caused the appearance of a factor in the NK cell supernatants capable of sustaining the formation of colonies of a larger size.

scholarly journals 799 Neoantigen-cytokine-chemokine multifunctional natural killer cell engager for immunotherapy of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A834-A834
Author(s):  
Xue Yao ◽  
Sandro Matosevic
Keyword(s):  
Tumor Microenvironment ◽  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Nk Cell Therapy

BackgroundThe effectiveness of natural killer (NK) cell-based immunotherapy against solid tumors is limited by the lack of specific antigens and the immunosuppressive tumor microenvironment (TME). Glioblastoma multiforme (GBM) is one such heavily immunosuppressive tumor that has been particularly hard to target and remains without a viable treatment. The development of novel approaches to enhance the efficacy of NK cells against GBM is urgently needed. NK cell engagers (NKCE) have been developed to enhance the efficacy of NK cell therapy.MethodsTo improve the clinical efficacy of NK cell therapy, we are developing a new generation of multi-specific killer engagers, which consists of a neoantigen-targeting moiety, together with cytokine and chemokine-producing domains. Neoantigens are new antigens formed specifically in tumor cells due to genome mutations, making them highly specific tools to target tumor cells. Our engager has been designed to target Wilms' tumor-1 (WT-1), a highly specific antigen overexpressed in GBM among other solid tumors. This is done through the generation of an scFv specific targeting the complex of WT-1126-134/HLA-A*02:01 on the surface of GBM. On the NK cell side, the engager is designed to target the activating receptor NKp46. Incorporation of the cytokine IL-15 within the engager supports the maturation, persistence, and expansion of NK cells in vivo while favoring their proliferation and survival in the tumor microenvironment. Additionally, our data indicated that the chemokine CXCL10 plays an important role in the infiltration of NK cells into GBM, however, GBM tumors produce low levels of this chemokine. Incorporation of a CXCL10-producing function into our engager supports intratumoral NK cell trafficking by promoting, through their synthetic production, increased levels of CXCL10 locally in the tumor microenvironment.ResultsCollectively, this has resulted in a novel multifunctional NK cell engager, combining neoantigen-cytokine-chemokine elements fused to an activating domain-specific to NK cells, and we have investigated its ability to support and enhance NK cell-mediated cytotoxicity against solid tumors in vitro and in vivo against patient-derived GBM models. The multi-specific engager shows both high tumor specificity, as well as the ability to overcome NK cell dysfunction encountered in the GBM TME.ConclusionsWe hypothesize that taking advantage of our multi-functional engager, NK cells will exhibit superior ex vivo expansion, infiltration, and antitumor activity in the treatment of GBM and other solid tumors.

scholarly journals Tissue Trafficking Kinetics of Rhesus Macaque Natural Killer Cells Measured by Serial Intravascular Staining

2022 ◽  
Vol 12 ◽  
Author(s):  
Ryland D. Mortlock ◽  
Chuanfeng Wu ◽  
E. Lake Potter ◽  
Diana M. Abraham ◽  
David S. J. Allan ◽  
...  
Keyword(s):  
Steady State ◽  
Nk Cells ◽  
Tissue Distribution ◽  
Natural Killer ◽  
Rhesus Macaque ◽  
Peripheral Blood ◽  
Cell Biology ◽  
Nk Cell ◽  
Lymphoid Tissues ◽  
Intravascular Staining

The in vivo tissue distribution and trafficking patterns of natural killer (NK) cells remain understudied. Animal models can help bridge the gap, and rhesus macaque (RM) primates faithfully recapitulate key elements of human NK cell biology. Here, we profiled the tissue distribution and localization patterns of three NK cell subsets across various RM tissues. We utilized serial intravascular staining (SIVS) to investigate the tissue trafficking kinetics at steady state and during recovery from CD16 depletion. We found that at steady state, CD16+ NK cells were selectively retained in the vasculature while CD56+ NK cells had a shorter residence time in peripheral blood. We also found that different subsets of NK cells had distinct trafficking kinetics to and from the lymph node as well as other lymphoid and non-lymphoid tissues. Lastly, we found that following administration of CD16-depleting antibody, CD16+ NK cells and their putative precursors retained a high proportion of continuously circulating cells, suggesting that regeneration of the CD16 NK compartment may take place in peripheral blood or the perivascular compartments of tissues.

scholarly journals Aggressive natural killer cell leukemia in an adult with establishment of an NK cell line

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 925-930 ◽  
Author(s):  
LA Fernandez ◽  
B Pope ◽  
C Lee ◽  
E Zayed
Keyword(s):  
Platelet Count ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Line ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Killer Cell ◽  
Chromosome 1 ◽  
Cell Leukemia ◽  
Wbc Count

Abstract There have been many reports of cases in which chronic increases in the numbers of natural killer (NK) cells have been reported. Whether this is reactive or neoplastic in nature has been debated. We report the first case of an aggressive NK cell leukemia in an adult with establishment of an NK cell line. A 70-year-old man had two spontaneous episodes of jejunal perforation and one month later developed a severe febrile illness with moderate splenomegaly. Hemoglobin was 13.1 g/L, and WBC count was 1.8 X 10(9)/L with 2% large granular lymphocytes (LGLs). Platelet count was 143 X 10(9)/L; prothrombin time (PT) and partial thromboplastin time (PTT) were normal. Bone marrow was infiltrated with 25% to 30% LGLs; serum lysozyme was normal. Serum LDH was initially 1,191 U/L and rose to 6,408 (normal 240 to 525 U/L). Ten days later, the WBC count increased to 99.9 X 10(9)/L with 70% LGL cells; the PT and PTT increased, and the platelet count dropped. No bacterial or viral cause of fever was identified. The cells from peripheral blood were LGLs that stained positively for acid phosphatase. All of the LGLs reacted with a monoclonal antibody reactive with NK cells (LEU-11b). Functionally, the patient's peripheral blood mononuclear cells (PBMs) demonstrated 100 times more lytic activity against K562 tumor cell lines than did normal PBMs. The patient's PBMs were propagated in vitro. The cultured cells showed the morphological, cytochemical, immunological, and functional characteristics of NK cells. In addition, partial trisomy involving chromosome 1 q with duplication in regions of q21 through q31 was observed in all metaphases analyzed. The extra chromosome 1q with duplication in regions q21 through q31 was translocated to the p- terminal of chromosome 5. One percent to 5% of normal PBMs comprise NK cells; in most cases, leukemias arise from normal phenotypic counterparts. This case demonstrated that aggressive NK cell leukemia may occur in adults. In addition, the chromosomal abnormalities suggest that this is not a reactive process but a malignancy.

scholarly journals Battle of Thermopylae: 300 Spartans (natural killer cells plus obinutuzumab) versus the immortal warriors (chronic lymphocytic leukemia cells) of Xerxes’ army

2019 ◽  
Vol 5 (10) ◽  
pp. FSO425
Author(s):  
Ricardo García-Muñoz ◽  
María-Josefa Nájera ◽  
Jesús Feliu ◽  
Judith Antón-Remírez ◽  
Enrique Ramalle-Gómara ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Killer Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Lymphokine Activated Killer Cells ◽  
Killer Cells

Aim: To analyze the effects of subcutaneous or intravenous rituximab + lymphokine-activated killer cells, obinutuzumab or ibrutinib on natural killer (NK) cell levels in chronic lymphocytic leukemia and follicular lymphoma patients. Patients & methods: The distribution of peripheral blood NK cells of 31 patients was analyzed by flow cytometry. Results: We detected a decrease of NK cells in peripheral blood below normal range after obinutuzumab treatment. During maintenance treatment with subcutaneous rituximab, an NK cell reduction was less pronounced than after intravenous rituximab treatment, despite lymphokine-activated killer cell infusions. Conclusion: After one dose of obinutuzumab, each NK cell in peripheral blood destroys 25 leukemic cells.

scholarly journals Functional Dichotomy in Natural Killer Cell Signaling

2001 ◽  
Vol 193 (12) ◽  
pp. 1413-1424 ◽  
Author(s):  
Francesco Colucci ◽  
Eleftheria Rosmaraki ◽  
Søren Bregenholt ◽  
Sandrine I. Samson ◽  
Vincenzo Di Bartolo ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Receptors ◽  
Nk T Cells ◽  
Nk Cell Differentiation ◽  
Ifn Γ

The product of the protooncogene Vav1 participates in multiple signaling pathways and is a critical regulator of antigen–receptor signaling in B and T lymphocytes, but its role during in vivo natural killer (NK) cell differentiation is not known. Here we have studied NK cell development in Vav1−/− mice and found that, in contrast to T and NK-T cells, the absolute numbers of phenotypically mature NK cells were not reduced. Vav1−/− mice produced normal amounts of interferon (IFN)-γ in response to Listeria monocytogenes and controlled early infection but showed reduced tumor clearance in vivo. In vitro stimulation of surface receptors in Vav1−/− NK cells resulted in normal IFN-γ production but reduced tumor cell lysis. Vav1 was found to control activation of extracellular signal-regulated kinases and exocytosis of cytotoxic granules. In contrast, conjugate formation appeared to be only mildly affected, and calcium mobilization was normal in Vav1−/− NK cells. These results highlight fundamental differences between proximal signaling events in T and NK cells and suggest a functional dichotomy for Vav1 in NK cells: a role in cytotoxicity but not for IFN-γ production.

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