Tumor Cell-Associated Tissue Factor Supports Metastatic Potential through Both NK Cell-Dependent and -Independent Mechanisms.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 66-66 ◽  
Author(s):  
Joseph Palumbo ◽  
Kelley A. Barney ◽  
Matthew J. Flick ◽  
Kathryn E. Talmage ◽  
Keith W. Kombrinck ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Tissue Factor ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Metastatic Potential ◽  
Hemostatic System ◽  
Hemostatic Factors

Abstract Multiple lines of evidence indicate that the hemostatic system contributes to cancer dissemination. Previous studies have shown that tumor cell-associated tissue factor (TF) expression is a crucial determinant of metastatic potential. Furthermore, we have shown that tumor cell-associated TF supports metastatic potential through mechanism(s) dependent on multiple circulating hemostatic system components, including prothrombin, platelets, fibrinogen and, more recently, fXIII. At least two of these circulating hemostatic factors (platelets and fibrinogen) have been shown to support metastatic potential by impeding the clearance of recently embolized tumor cells by natural killer (NK) cells. It is reasonable to hypothesize that tumor cell-associated TF expression also supports metastatic potential by a mechanism coupled to NK cell function. Here, we used C57BL/6-derived, Ras-transformed tumor cell lines expressing wildtype murine tissue factor (TFWT), a mutant TF lacking the intracytoplasmic portion (TFΔTail), or no tissue factor (TFO) to directly examine the interplay between tumor cell-associated TF and NK cell function in determining metastatic potential. Each of these cell lines was capable of robust, comparable tumor growth in wildtype C57BL/6 mice. Loss of either platelet function or fibrinogen significantly diminished the metastatic potential of TFWT cells, but this effect was entirely abrogated by the concomitant loss of NK cells. Similar results were obtained with TFΔTail cells, indicating that the cytoplasmic portion of TF is not critical to these interactions. To determine if the increase in metastatic potential conferred by tumor cell-associated TF expression is entirely linked to NK cell function, we compared the metastatic potential and early survival of TFWT and TFO cells in mice with and without NK cells. TFOcells rarely formed any visible metastatic foci in mice with intact NK cell function, while TFWT cells were aggressively metastatic. Importantly, TF expression remained a significant determinant of metastatic potential even in mice lacking NK cells. Comparisons of the early fate of TFWT and TFO cells revealed that TF expression was not a determinant of initial tumor cell localization within the lungs. Rather, TF expression supported the sustained adherence and/or survival of tumor cells. Taken together, these data indicate that one mechanism linking tumor cell-associated TF expression to metastatic potential is coupled to circulating hemostatic factors and results in impaired NK cell-mediated clearance of recently established micrometastatic foci. However, TF expression also supports metastasis by at least one additional mechanism that is independent of natural killer cell function.

Hemostatic Factors Contribute to Tumor Cell Metastatic Potential by a Mechanism Linked to Natural Killer Cell Function.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 690-690 ◽  
Author(s):  
Joseph S. Palumbo ◽  
Kathryn E. Talmage ◽  
Jessica V. Massari ◽  
Christine M. La Jeunesse ◽  
Matthew J. Flick ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Tumor Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Platelet Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Metastatic Potential ◽  
Natural Killer Cell Function

Abstract A linkage between hemostatic system components and tumor cell metastatic potential has been well established, but the underlying mechanism(s) by which various circulating and cell-associated coagulation factors and platelets promote tumor cell dissemination remains to be fully defined. One potential mechanism by which tumor cell-associated microthrombi might enhance metastatic potential is by interfering with the cytolytic elimination of tumor cell emboli by natural killer (NK) cells. In order to explore this hypothesis, we studied tumor dissemination in mice lacking either fibrinogen or Gαq, a G protein critical for platelet activation. Comparative studies of experimental lung metastasis in control and Gαq−/− mice showed that loss of platelet activation resulted in a two-orders-of-magnitude decrease in pulmonary metastatic foci formed by either Lewis lung carcinoma or B16 melanoma. The difference in metastatic success was not the result of differences in tumor growth rate, as tumors transplanted into the dorsal subcutis of Gαq−/− and wildtype animals grew at similar rates. Rather, tumor cell fate analyses using radiolabeled tumor cells showed that the survival of tumor cells within the lung was significantly improved in mice that retained platelet activation function relative to Gαq−/− mice with a profound platelet activation defect. In order to examine the potential interplay between platelet activation and natural killer cell function, we compared pulmonary tumor cell survival in cohorts of control and Gαq−/− mice immuno-depleted of NK cells with an anti-asialo GM1 antibody. Remarkably, platelet function was no longer a determinant of metastatic potential in mice lacking NK cells. Given that fibrin(ogen) is also an established determinant of metastatic success we explored whether the influence of this key hemostatic factor on tumor cell dissemination was also mechanistically-coupled to natural killer cell function. We interbred fibrinogen-deficient mice with Gz-Ly49A transgenic mice known to have a constitutive deficit in NK cells. In those cohorts of mice with normal NK cells, we affirmed the earlier finding that fibrinogen deficiency resulted in a significant diminution in metastatic potential. However, consistent with our findings in mice with defective platelet activation, fibrinogen was found to no longer be a determinant of metastatic potential in mice lacking NK cells. These data establish another important link between innate immune surveillance and the hemostatic system. Further, it appears that at least one mechanism by which tumor cell-associated microthrombi increase metastatic potential is by restricting NK cell-mediated tumor cell elimination. Given that NK cell cytotoxicity requires direct contact with any target cell, one attractive model presently being explored is that tumor cell-associated platelets physically block NK cell access to tumor cell emboli.

Mechanisms Coupling Thrombin-Mediated Proteolysis to Metastasis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-22-sci-22
Author(s):  
Joseph S. Palumbo
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Tumor Stroma ◽  
Metastatic Potential ◽  
Coagulation Factors ◽  
Protease Activated Receptors ◽  
Multiple Substrates ◽  
Hemostatic Factors

Multiple lines of evidence point to a link between coagulation factors and malignancy. Numerous clinical studies have demonstrated a strong correlation between tumor cell-associated tissue factor (TF) expression and poor outcome for many types of cancer. While TF expression by tumor cells could promote metastasis through several mechanisms, comparative analyses of TF-sufficient and TF-deficient tumor cell lines in mice with and without key circulating hemostatic factors point to thrombin as the premier downstream effector coupling TF to metastasis. Furthermore, it appears that thrombin supports metastasis through mechanism(s) that are highly dependent on the availability of fibrinogen, factor XIII, and platelet function. The metastatic potential of TF-expressing tumor cells has been shown to be strongly diminished in mice with genetic defects in either fibrin formation or stabilization (e.g., Fib−/−, fXIII−/−), or platelet disorders (e.g., NF-E2−/−, Gαq−/−, PAR-4−/−). Interestingly, one mechanism through which tumor-cell-associated TF, prothrombin, and the platelet/fibrinogen axis all appear to support metastasis is by impeding natural killer (NK) cell-mediated clearance of newly formed micrometastases. While these results demonstrate a novel link between the hemostatic and innate immune systems, limiting NK cell function is clearly not the only mechanism coupling thrombin to tumor cell metastasis. Signaling through protease activated receptors (PARs) on cells other than platelets has been suggested to support tumor stroma formation and angiogenesis. Furthermore, thrombin-mediated signaling via PARs expressed by tumor cells themselves has been shown to support metastatic potential. Finally, thrombin may support metastatic potential by acting in concert on multiple substrates (e.g., platelet and endothelial cell-associated PARs, fibrinogen, fXIII, etc.) to promote the sustained, stable adherence of circulating tumor cells in distant vascular beds. In summary, thrombinmediated proteolysis appears to influence both extracellular and intracellular events vital to tumor cell dissemination. Therapeutic strategies designed to block tumor cell-associated thrombin generation/activity could prove effective in preventing or eliminating metastatic disease.

Factor XIII Supports Metastatic Potential through a Mechanism Coupled to Natural Killer Cell Function.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1753-1753
Author(s):  
Joseph S. Palumbo ◽  
Kelley A. Barney ◽  
Elizabeth A. Williams ◽  
Maureen A. Shaw ◽  
Anjali Mishra ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Cell Survival ◽  
Nk Cells ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Metastatic Potential ◽  
Wild Type ◽  
Tumor Cell Survival

Abstract Interplay between the hemostatic and innate immune systems appears to be an important determinant of tumor metastasis. Studies of mice with selected hemostatic and/or immunological deficits have been particularly revealing, and indicate that platelets and fibrinogen support metastatic potential in part by impeding the clearance of newly formed micrometastases by natural killer (NK) cells. A key step in the formation of stable platelet/fibrin thrombi is the fXIII-mediated cross-linking of fibrin matrices. In order to examine the role of fXIII in tumor dissemination in detail, we studied tumor growth and metastasis in gene-targeted mice lacking the catalytic fXIII-A subunit (fXIII−/−). Comparative analyses of experimental lung metastases in immunocompetent fXIII−/− and wild-type mice showed that elimination of fXIII diminished the metastatic potential of both Lewis lung carcinoma (LLC) and B16-BL6 melanoma cells 5- to 10-fold. Loss of fXIII activity also significantly diminished tumor cell metastatic potential in spontaneous metastasis assays in which lung and liver lesions were quantified ∼2 weeks after resection of primary subcutaneous tumors. These differences were not the result of any genotype-dependent difference in tumor growth, as tumors transplanted into the dorsal subcutis of fXIII−/− and control mice grew at similar rates. In order to determine if fXIII was coupled to metastasis by a mechanism linked to NK cell function, we compared the early fate/survival of radiolabeled LLC cells in cohorts of fXIII−/− and wild-type mice pretreated with either an anti-asialo GM1 antibody known to deplete NK cells or control Ig. Here, the residual radiolabel present within lungs, blood and abdominal organs was measured 30 minutes or 26 hours after injection. Neither loss of fXIII nor NK cells had any impact on the initial localization of tumor cells within the lungs. The majority of the inoculum (∼90%) was present in the lungs 30 minutes after intravenous inoculation, with only scant amounts present in the other organs evaluated, regardless of mouse genotype or antibody treatment. Twenty-six hours after injection, fXIII deficiency resulted in a significant diminution in the apparent number of tumor cells remaining in the lungs in mice with intact NK cells. However, in mice immunologically depleted of NK cells, fXIII ceased to be a determinant of early tumor cell survival. These analyses identify fXIII as a significant determinant of metastatic potential and indicate that at least one mechanism whereby fXIII increases metastatic success is by impeding NK cell-mediated clearance of tumor cells. Given that these findings closely parallel previous observations made in fibrinogen-deficient mice, an attractive but still unproven model is that fXIII-mediated stabilization of fibrin/platelet aggregates associated with newly-formed micrometastases increases tumor cell survival in large part by limiting NK cell function. These studies also suggest that therapeutic strategies directed at fXIII might be useful in limiting malignant disease.

scholarly journals The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti–PD-1 antibody

Blood ◽  
2010 ◽  
Vol 116 (13) ◽  
pp. 2286-2294 ◽  
Author(s):  
Don M. Benson ◽  
Courtney E. Bakan ◽  
Anjali Mishra ◽  
Craig C. Hofmeister ◽  
Yvonne Efebera ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune Response ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Immune Response ◽  
Cell Versus

Abstract T-cell expression of programmed death receptor-1 (PD-1) down-regulates the immune response against malignancy by interacting with cognate ligands (eg, PD-L1) on tumor cells; however, little is known regarding PD-1 and natural killer (NK) cells. NK cells exert cytotoxicity against multiple myeloma (MM), an effect enhanced through novel therapies. We show that NK cells from MM patients express PD-1 whereas normal NK cells do not and confirm PD-L1 on primary MM cells. Engagement of PD-1 with PD-L1 should down-modulate the NK-cell versus MM effect. We demonstrate that CT-011, a novel anti–PD-1 antibody, enhances human NK-cell function against autologous, primary MM cells, seemingly through effects on NK-cell trafficking, immune complex formation with MM cells, and cytotoxicity specifically toward PD-L1+ MM tumor cells but not normal cells. We show that lenalidomide down-regulates PD-L1 on primary MM cells and may augment CT-011's enhancement of NK-cell function against MM. We demonstrate a role for the PD-1/PD-L1 signaling axis in the NK-cell immune response against MM and a role for CT-011 in enhancing the NK-cell versus MM effect. A phase 2 clinical trial of CT-011 in combination with lenalidomide for patients with MM should be considered.

scholarly journals Tumor cell–associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell–dependent and–independent mechanisms

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 133-141 ◽  
Author(s):  
Joseph S. Palumbo ◽  
Kathryn E. Talmage ◽  
Jessica V. Massari ◽  
Christine M. La Jeunesse ◽  
Matthew J. Flick ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Tumor Cell ◽  
Natural Killer ◽  
Tissue Factor ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Killer Cell ◽  
Metastatic Potential ◽  
Cytoplasmic Domain ◽  
Hemostatic Factors

Tumor cell–associated tissue factor (TF) is a powerful determinant of metastatic potential. TF may increase metastasis by supporting thrombin-mediated proteolysis, through intracellular signaling events mediated by the TF cytoplasmic domain, through TF/fVIIa/fXa–mediated activation of protease-activated receptors, or through a combination of these processes. To better define the relationship between tumor cell-associated TF and circulating hemostatic factors in malignancy, we generated a set of C57Bl/6-derived tumor lines genetically lacking TF, expressing wild-type murine TF, or expressing a mutant TF lacking the cytoplasmic domain. Comparison of the metastatic potential of these cells in immunocompetent mice with genetic deficits in prothrombin, platelet function, or fibrinogen revealed that TF supports metastasis through mechanisms independent of the cytoplasmic domain, but dependent on each of these distal hemostatic factors. TF was neither required for primary tumor growth nor necessary for initial localization of embolized tumor cells within the lungs. Rather, tumor cell fate studies indicated TF supports metastasis by increasing the survival of micrometastases. One mechanism linking TF to metastasis is through a fibrin(ogen)-dependent and platelet-dependent restriction in natural killer cell–mediated clearance of micrometastases. However, TF also supported the early success of micrometastases through an additional mechanism independent of natural killer cells, but coupled to circulating prothrombin.

Thrombin Control Mechanisms and Thrombin Targets in Cancer Biology

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-17-SCI-17
Author(s):  
Jay L. Degen ◽  
Joseph S. Palumbo
Keyword(s):  
Tumor Cell ◽  
Tissue Factor ◽  
Tumor Cells ◽  
Cancer Biology ◽  
Malignant Progression ◽  
Wild Type ◽  
Hemostatic System ◽  
System Components ◽  
Hemostatic Factors

Abstract SCI-17 A link between hemostasis and cancer has been recognized for more than a century, but the last decade has seen substantial strides in understanding the mechanisms by which hemostatic system components actively contribute to the malignant phenotype. The expression of procoagulants, such as tissue factor (TF), by tumor cells has been shown to be a poor prognostic factor in clinical studies and a crucial determinant of metastasis in animal models. While TF expressed by tumor cells likely plays a multifaceted role in cancer biology, a substantial body of evidence indicates that tumor cell-associated and circulating hemostatic system components (e.g., prothrombin, fibrinogen, platelets) play a cooperative role in supporting metastasis. The capacity of tumor cells to generate thrombin has been proposed to support metastasis through several mechanisms, including tumor cell proliferation, stable adhesion, regulation of apoptosis, and escape from innate immune surveillance mechanisms. More recently, the fundamental importance of endothelial regulators of thrombin activity in metastasis was established through studies of tumor dissemination in mice expressing mutant forms of thrombomodulin (TM). Mice expressing a TM derivative with reduced thrombin affinity (TMPro) exhibited a profoundly prometastatic phenotype relative to wild-type (WT) mice. The TMPro mutation was shown to support metastasis by promoting the survival of tumor cell emboli newly localized to the lung. The impact of the TMPro mutation on metastasis was dependent on tumor cell-associated tissue factor, prothrombin, thrombin function, and platelets. In contrast, mice expressing a mutant form of TM lacking the lectin-like domain (TMLed) that were shown previously to have altered immune function but normal thrombin affinity, exhibited metastatic potential comparable to wild-type mice. These studies further highlight the importance of the hemostatic system in metastasis and demonstrate that apart from tumor cell-associated and circulating procoagulants, TM-mediated regulation of hemostatic function strongly influences tumor cell metastatic success. In addition, recent studies of inflammation-driven cancer have revealed that the role of hemostatic factors in tumor biology is not limited to later phases of malignant progression, such as metastasis. Fibrin(ogen)-mediated regulation of leukocyte function was shown to support tumor development and tumor proliferation in a murine model of inflammation-driven colon cancer. Recent advances in our understanding of the role of hemostatic factors in cancer biology demonstrate that this system of proteins can be important in multiple phases of malignant progression, and underscore the potential utility of targeting selected coagulation factors as a novel adjunct therapy in the treatment of cancer. Disclosures: Palumbo: Novo Nordisk Corporation: Research Funding.

Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell–mediated elimination of tumor cells

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 178-185 ◽  
Author(s):  
Joseph S. Palumbo ◽  
Kathryn E. Talmage ◽  
Jessica V. Massari ◽  
Christine M. La Jeunesse ◽  
Matthew J. Flick ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Natural Killer ◽  
Tumor Cells ◽  
Platelet Activation ◽  
Cell Function ◽  
Killer Cell ◽  
Metastatic Potential ◽  
Pulmonary Vasculature ◽  
Tumor Dissemination ◽  
Hemostatic Factors

Abstract To test the hypothesis that platelet activation contributes to tumor dissemination, we studied metastasis in mice lacking Gαq, a G protein critical for platelet activation. Loss of platelet activation resulted in a profound diminution in both experimental and spontaneous metastases. Analyses of the distribution of radiolabeled tumor cells demonstrated that platelet function, like fibrinogen, significantly improved the survival of circulating tumor cells in the pulmonary vasculature. More detailed studies showed that the increase in metastatic success conferred by either platelets or fibrinogen was linked to natural killer cell function. Specifically, the pronounced reduction in tumor cell survival observed in fibrinogen- and Gαq-deficient mice relative to control animals was eliminated by the immunologic or genetic depletion of natural killer cells. These studies establish an important link between hemostatic factors and innate immunity and indicate that one mechanism by which the platelet-fibrin(ogen) axis contributes to metastatic potential is by impeding natural killer cell elimination of tumor cells.

543 Natural killer cells restrict the growth of liver metastases in nude hosts

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A579-A579
Author(s):  
Alexandra Quackenbush ◽  
Pepper Schedin
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Liver Metastases ◽  
Nk Cells ◽  
Natural Killer ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Nk Cell ◽  
Cell Depletion

BackgroundCancer patients with liver metastases have limited treatment options, especially as only 15–20% are eligible for curative-intent surgical resection.1 Unfortunately, liver metastases also seem to be poorly responsive to immune checkpoint inhibitors (ICI)].2 3 It could be that the unique immunological hallmarks of the liver, including resident macrophages and significant numbers of NK and NKT cells, create a tumor microenvironment that is best suited to alternative forms of immunotherapy that do not rely exclusively on ICI.MethodsWe investigated how the presence of T, natural killer (NK), and NKT cells impact overt liver metastases using a model in which tumor cells are delivered to the liver via intraportal injection to hosts that were either wiltype, nude, or nude with NK-depletion. NK cell depletion was achieved via administration of anti-asialo GM1 antibody 2 days before tumor cell injection and for the duration of the experiment until endpoint at 6 weeks post tumor cell injection, with NK cell depletion confirmed by flow cytometry. Tumors were assessed histologically.ResultsUsing the portal vein model in female nulliparous mice, overt liver metastasis incidence was about 30% across 2 different mammary tumor cell lines. The incidence rose to 80–100% when tumor cells were delivered to hosts in the post-wean window (referred to as involution hosts), mirroring increased breast cancer metastasis to the liver observed in postpartum breast cancer patients.4 Conversely, when tumor cells were delivered to nude hosts, either nulliparous or involution stages, the incidence of metastases dropped to 0–10%. Importantly, tumor cells injected into the mammary gland of nude mice grew robustly with 100% take. Nude hosts lack T cells and NKT cells; however, NK cells are present. Furthermore, the liver is enriched for NK cells, whilst the mammary gland has few NK cells.5 We hypothesized that NK cells, when in the background of T- and NKT-cell depletion (i.e. nude host), restrict outgrowth of mammary tumor cells in the liver. Six weeks after portal vein injection of mammary tumor cells to nude hosts we find increased incidence of metastasis in the NK-depleted group compared to isotype control, as well as increased number of metastases per mouse.ConclusionsOur data suggest that NK cells play an important role in controlling liver metastases in nude hosts, and that NK activity in wild type hosts is insufficient to control liver metastases. Increasing NK cell cytotoxic activity could be an effective immunotherapy strategy to control liver metastases.ReferencesNordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, et al: Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol 2013;14(12):1208–1215.Bilen MA, Shabto JM, Martini DJ, Liu Y, Lewis C, Collins H, Akce M, Kissick H, Carthon BC, Shaib WL, et al: Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy. BMC Cancer 2019;19(1):857.Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Sosman JA, Atkins MB, Leming PD, et al: Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab. JAMA Oncol 2019.Goddard ET, Hill RC, Nemkov T, D’Alessandro A, Hansen KC, Maller O, Mongoue-Tchokote S, Mori M, Partridge AH, Borges VF, et al: The rodent liver undergoes weaning-induced involution and supports breast cancer metastasis. Cancer Discov 2017;7(2):177–187.Shi FD, Ljunggren HG, La Cava A, Van Kaer L. Organ-specific features of natural killer cells. Nat Rev Immunol 2011;11(10):658–671.

scholarly journals CD38 contributes to human natural killer cell responses through a role in immune synapse formation

2018 ◽  
Author(s):  
Mathieu Le Gars ◽  
Christof Seiler ◽  
Alexander W. Kay ◽  
Nicholas L. Bayless ◽  
Elsa Sola ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synapse Formation ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Target Cells ◽  
Immune Synapse ◽  
Ifn Γ

AbstractNatural killer (NK) cells use a diverse array of activating and inhibitory surface receptors to detect threats and provide an early line of defense against viral infections and cancer. Here, we demonstrate that the cell surface protein CD38 is a key human NK cell functional receptor through a role in immune synapse formation. CD38 expression marks a mature subset of human NK cells with a high functional capacity. NK cells expressing high levels of CD38 display enhanced killing and IFN-γ secretion in response to influenza virus-infected and tumor cells. Inhibition of CD38 enzymatic activity does not influence NK cell function, but blockade of CD38 and its ligand CD31 abrogates killing and IFN-γ expression in response to influenza-infected cells. Blockade of CD38 on NK cells similarly inhibits killing of tumor cells. CD38 localizes and accumulates at the immune synapse between NK cells and their targets, and blocking CD38 severely abrogates the ability of NK cells to form conjugates and immune synapses with target cells. Thus, CD38 plays a critical role in NK cell immune synapse formation. These findings open new avenues in immunotherapeutic development for cancer and infection by revealing a critical role for CD38 in NK cell function.

scholarly journals Chemiluminescence response of human natural killer cells. I. The relationship between target cell binding, chemiluminescence, and cytolysis.

1982 ◽  
Vol 156 (2) ◽  
pp. 492-505 ◽  
Author(s):  
S L Helfand ◽  
J Werkmeister ◽  
J C Roder
Keyword(s):  
Tumor Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Cell Lines ◽  
Target Cell ◽  
Nk Cell ◽  
Target Antigen ◽  
Target Cells ◽  
Tumor Cell Lines

The binding of tumor cells or fetal fibroblasts to human natural killer (NK) cells led to a rapid chemiluminescence response within seconds of target-effector interaction. The degree of chemiluminescence was dependent on the concentration of NK-enriched lymphocytes or target cells, and plasma membrane vesicles from K562 also induced a chemiluminescence response. Mild glutaraldehyde treatment of effector cells abrogated their ability to generate chemiluminescence, whereas K562 target cells treated in the same way were almost fully able to induce a chemiluminescence response to NK-enriched lymphocytes. These results show a directionality of response with NK as the responders and tumor cells as the stimulators. A survey of eight different tumor cell lines and fetal fibroblast lines revealed a striking correlation (r greater than 0.93, P less than 0.001) between the ability of a given line to bind to NK-enriched lymphocytes, induce chemiluminescence, and to be lysed. Three differentiated sublines of K562 grown in butyrate and cloned induced little chemiluminescence compared with the K562 parent, and they were selectively resistant to NK-mediated binding and cytolysis. In addition, treatment of K562 cells with higher concentrations of glutaraldehyde for longer periods led to varying degrees of target antigen preservation, as measured in cold target competition assays and in conjugate formation. The degree of NK target antigen preservation correlated directly with the ability of the cells to induce chemiluminescence (r greater than 0.95). The degree of NK activation was also important because interferon-pretreated effectors generated more chemiluminescence upon stimulation with K562 or MeWo targets. Monocytes or granulocytes did not contribute to the chemiluminescence induced by NK-sensitive targets. Some NK-resistant tumor cell lines were sensitive to monocyte-mediated cytolysis and also induced chemiluminescence in monocytes but not NK cells. These results show that the target structures recognized by the NK cell may play a role in NK activation because the degree of chemiluminescence was directly proportional to the ability of a given target cell line to bind to the NK cell and to be lysed.

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