Highly functional natural killer (NK) cells as predictive biomarkers associated with long response to castration in newly diagnosed metastatic prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 95-95
Author(s):  
Christine Pasero ◽  
Gwenaelle Gravis ◽  
Mathilde Guerin ◽  
Palma Rocchi ◽  
Jeanne Thomassin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nk Cells ◽  
Natural Killer ◽  
Metastatic Prostate Cancer ◽  
Nk Cell ◽  
Predictive Biomarkers ◽  
Newly Diagnosed ◽  
Cell Receptors ◽  
Nk Cell Receptors ◽  
Activating Receptors

95 Background: Immunotherapy is now investigated as a promising alternative treatment for patients (pts) with metastatic prostate cancer (PC). Natural killer (NK) cells are powerful effector cells with antitumoral activity and their role have been explored in solid tumors but not yet in prostate cancer. NK cell cytotoxicity is regulated by a balance between activating and inhibitory receptors. Here, we performed a restrospective study to evaluate the link between NK cells and the time of castration response in newly diagnosed PC patients with metastases. Methods: Newly diagnosed metastatic PC pts were divided according the time of castration response, with an 18-months cutoff value: 18 pts with long castration response (LCR, median = 64.6 months), and 14 pts with short castration response ([SCR] median = 11.2 months), with a median overall survival of 97.7 months and 33.8 months respectively. Circulating NK cells from these patients were studied by flow cytometry to evaluate the expression of activating receptors and the NK cell functionality. Results: We observed thatNK cells from LCR pts express higher levels of the maturation marker CD57 (43.3% vs. 23.3% positive cells, p= 0.002), the receptor CD16 involved in cytotoxicity (29,124 vs. 16,806 MFI, p= 0.02), and the activating receptors NKp46 and NKp30 (17.5 vs. 11.4 RMFI, p= 0.0146 , and 10.9 vs. 6.3 RMFI, p = 0.0128 respectively) than NK cells from SCR pts. This suggests that LCR pts have powerful NK cells. Indeed, NK cells from LCR pts are highly efficient in CD107 functional assay than NK cells from SCR pts (28.9% vs. 19.4%, p =0.002). In vitro blocking experiments show that NKp46 is precisely one of the NK cell receptors involved in the NK-mediated recognition of prostate tumor cells, thus higher expression of NKp46 would help to control PC progression. Conclusions: Together our results show for the first time that efficient NK cells are associated to a long response to castration and prolonged survival in newly diagnosed metastatic PC. NK cell receptors might be useful as predictive biomarkers in metastatic PC, to help in stratification of patients and to design NK cell–based immunotherapeutic strategies for PC.

Highly functional natural killer (NK) cells as predictive biomarkers associated to long response to castration in newly diagnosed metastatic prostate cancer.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. e16025-e16025
Author(s):  
Christine Pasero ◽  
Gwenaelle Gravis ◽  
Mathilde Guerin ◽  
Palma Rocchi ◽  
Jeanne Thomassin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nk Cells ◽  
Natural Killer ◽  
Metastatic Prostate Cancer ◽  
Predictive Biomarkers ◽  
Newly Diagnosed

Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 1935-1947 ◽  
Author(s):  
Sherif S. Farag ◽  
Todd A. Fehniger ◽  
Loredana Ruggeri ◽  
Andrea Velardi ◽  
Michael A. Caligiuri
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Natural Cytotoxicity ◽  
Receptor Ligand ◽  
Cell Receptors ◽  
Nk Cell Receptors ◽  
Ligand Interactions ◽  
Nk Receptor

AbstractNatural killer (NK) cells have held great promise for the immunotherapy of cancer for more than 3 decades. However, to date only modest clinical success has been achieved manipulating the NK cell compartment in patients with malignant disease. Progress in the field of NK cell receptors has revolutionized our concept of how NK cells selectively recognize and lyse tumor and virally infected cells while sparing normal cells. Major families of cell surface receptors that inhibit and activate NK cells to lyse target cells have been characterized, including killer cell immunoglobulinlike receptors (KIRs), C-type lectins, and natural cytotoxicity receptors (NCRs). Further, identification of NK receptor ligands and their expression on normal and transformed cells completes the information needed to begin development of rational clinical approaches to manipulating receptor/ligand interactions for clinical benefit. Indeed, clinical data suggest that mismatch of NK receptors and ligands during allogeneic bone marrow transplantation may be used to prevent leukemia relapse. Here, we review how NK cell receptors control natural cytotoxicity and novel approaches to manipulating NK receptor-ligand interactions for the potential benefit of patients with cancer.

scholarly journals Research Progress on NK Cell Receptors and Their Signaling Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Yingying Chen ◽  
Dan Lu ◽  
Alexey Churov ◽  
Rong Fu
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Signaling Pathways ◽  
Nk Cell ◽  
Research Progress ◽  
Inhibitory Receptors ◽  
Cell Receptors ◽  
Surface Receptors ◽  
Nk Cell Receptors ◽  
Activating Receptors

Natural killer cells (NK cells) play an important role in innate immunity. NK cells recognize self and nonself depending on the balance of activating receptors and inhibitory receptors. After binding to their ligands, NK cell receptors trigger subsequent signaling conduction and then determine whether NK is activated or inhibited. Furthermore, NK cell response includes cytotoxicity and cytokine release, which is tightly related to the activation of NK cell-activating receptors and the inhibition of inhibitory receptors on the surfaces of NK cells. The expression and function of NK cell surface receptors also alter in virus infection, tumor, and autoimmune diseases and influence the occurrence and development of diseases. So, it is important to understand the mechanism of recognition between NK receptors and their ligands in pathological conditions and the signaling pathways of NK cell receptors. This review mainly summarizes the research progress on NK cell surface receptors and their signal pathways.

scholarly journals Super-resolution imaging of remodeled synaptic actin reveals different synergies between NK cell receptors and integrins

Blood ◽  
2012 ◽  
Vol 120 (18) ◽  
pp. 3729-3740 ◽  
Author(s):  
Alice C. N. Brown ◽  
Ian M. Dobbie ◽  
Juha-Matti Alakoskela ◽  
Ilan Davis ◽  
Daniel M. Davis
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Three Dimensional ◽  
Super Resolution ◽  
Cortical Actin ◽  
Cell Receptors ◽  
Lytic Granules ◽  
Nk Cell Receptors ◽  
Activating Receptors ◽  
Ifn Γ

Abstract Natural killer (NK) cells secrete lytic granules to directly kill virus-infected or transformed cells and secrete cytokines to communicate with other cells. Three-dimensional super-resolved images of F-actin, lytic granules, and IFN-γ in primary human NK cells stimulated through different activating receptors reveal that both IFN-γ and lytic granules accumulated in domains where the periodicity of the cortical actin mesh at the synapse opened up to be penetrable. Ligation of some activating receptors alone (eg, CD16 or NKG2D) was sufficient to increase the periodicity of the actin mesh, but surprisingly, ligation of others (eg, NKp46 or CD2) was not sufficient to induce cortical actin remodeling unless LFA-1 was coligated. Importantly, influenza virus particles that can be recognized by NK cells similarly did not open the actin mesh but could if LFA-1 was coligated. This leads us to propose that immune cells using germline-encoded receptors to directly recognize foreign proteins can use integrin recognition to differentiate between free pathogens and pathogen-infected cells that will both be present in blood. This distinction would not be required for NK cell receptors, such as NKG2D, which recognize host cell–encoded proteins that can only be found on diseased cells and not pathogens.

scholarly journals Enhancing Natural Killer Cell-Mediated Lysis of Lymphoma Cells By Combining Therapeutic Antibodies with CD20-Specific Immunoligands Engaging NKG2D or NKp30

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1779-1779
Author(s):  
Matthias Peipp ◽  
Christian Kellner ◽  
Andreas Günther ◽  
Andreas Humpe ◽  
Roland Repp ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Nk Cell ◽  
Autologous Tumor ◽  
Therapeutic Antibodies ◽  
Single Chain ◽  
Lymphoma Cells ◽  
Cell Receptors ◽  
Nk Cell Receptors

Abstract Antibody-dependent cell-mediated cytotoxicity (ADCC) represents a major effector function of many therapeutic antibodies. Thus, enhancing ADCC is a promising approach to further improve antibody therapy. Here, the CD20-specific immunoligands ULBP2:7D8 and B7-H6:7D8, which engage the stimulatory NK cell receptors natural killer group 2 member D (NKG2D) and NKp30, respectively, were compared for their abilities to boost ADCC in an attempt to design an effective antibody combination strategy. The immunoligands are designed as single chain molecules, with a single chain fragment variable (scFv) of the CD20 antibody 7D8 fused to UL16-binding protein (ULBP) 2 or B7 homologue 6 (B7-H6), which are ligands of the activating NK cell receptors NKG2D and NKp30, respectively. By binding to lymphoma cells the immunoligands designated as ULBP2:7D8 and B7-H6:7D8 mimicked an induced self phenotype and thereby triggered NK cells to kill lymphoma and leukemia cells. Both immunoligands augmented ADCC by NK cells synergistically when combined with the lymphoma-directed antibodies rituximab or daratumumab recognizing CD20 and CD38, respectively. Antibody combinations with ULBP2:7D8 resulted in higher cytotoxicity (up to 10-fold lower EC50-values) in comparison to combinations with B7-H6:7D8, which in individual experiments failed to boost ADCC. Thus, NK cells were triggered more efficiently when NKG2D rather than NKp30 was co-ligated together with FcγRIIIA. Although a combination of ULBP2:7D8 and B7-H6:7D8 produced synergistic effects, no significant improvements were obtained by combining the three agents rituximab, B7-H6:7D8 and ULBP2:7D8. Enhancement of ADCC by the immunoligands was also achieved when NK cells from lymphoma or leukemia patients were analyzed as effector cells. ULBP2:7D8 in particular increased lysis not only of allogeneic but also of autologous tumor cells. In summary, co-targeting of NKG2D was more effective in promoting NK cell-mediated ADCC than co-ligation of NKp30 and may represent a promising approach to further enhance the efficacy of therapeutic antibodies. Based on these results we propose a ‘dual-dual-targeting’ concept by co-targeting of two surface antigens on tumor cells and concomitant engagement of two different activating NK cell receptors. Disclosures van de Winkel: Genmab BV: Employment, Patents & Royalties. Parren:Genmab: Employment, Equity Ownership.

Increased Expression of Activating Receptors on NK Cells in the Post-Transplant Period.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1249-1249
Author(s):  
Michael Boyiadzis ◽  
Jesse M. Carson ◽  
Sarfraz A. Memon ◽  
Robert Dean ◽  
Kate Castro ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Hematopoietic Stem ◽  
Lectin Receptors ◽  
Cell Receptors ◽  
Post Transplant ◽  
Lectin Receptor ◽  
Receptor Repertoire ◽  
Nk Cell Receptors ◽  
Activating Receptors

Abstract Following allogeneic and autologous hematopoietic stem cell transplantation (HSCT) natural killer (NK) cells are among the first lymphocyte populations to recover, returning to normal levels within one month after HSCT. We previously reported that levels of IL-15, a cytokine critical to NK cell homeostasis, are elevated during the peri-transplant period (ASH, 2003). Modulation of the relative frequency and intensity of expression of the activating NK cell receptors by IL-15 may contribute to NK-mediated cytotoxicity post transplant. We compared the expression of activating NK receptors in the donor apheresis product and in recipient peripheral blood at one and three months following reduced intensity allogeneic HSCT from HLA-matched siblings. NK cells, divided into CD56bright CD16− and CD56dimCD16+ subsets, were assessed for receptors that trigger cytotoxicity: the natural cytotoxicity receptors (NCR) NKp30 and NKp46, and the C-type lectin receptors NKG2D and NKG2C-CD94. During the first post transplant month the NK cell numbers recovered to normal levels, but the CD56brightCD16− subset increased disproportionately (p = .005). By three months the proportions of the NK cell subsets returned to pre-transplant levels. In both NK subsets, the percentage of cells expressing NCR NKp46 or NKp30 doubled by one month and was sustained at three months. The percentage of cells expressing the C-type lectin receptor CD94 similarly increased by 50% in both NK subsets. The heterodimeric activating partner of CD94, NKG2C, was also increased, but the increase in frequency of cells expressing this receptor was less than those pairing CD94 with its inhibitory NKG2A partner. The homodimeric activating receptor NKG2D increased in the NK CD56brightCD16− subset, but did not significantly change in the CD56dim CD16+ NK population. Consistent with responsiveness to elevated IL-15 during the peri-transplant period, expression of both the IL-2/IL-15 beta and common gamma receptors increased at one and three months. Furthermore, when NK cells from normal donors were cultured with IL-15, we observed both a population shift towards CD56brightCD16− and an up-regulation of the NK cell activating receptors, similar to the changes observed during the early post transplant period. These results suggest that IL-15-dependent changes in NK subset distribution and activating NK receptor repertoire occur during the early post-transplant period. Up-regulation of activating NK cell receptors may contribute to NK cell anti-tumor efficacy in the post transplant period.

scholarly journals Natural Killer Cell Mobilization in Breast and Prostate Cancer Survivors: The Implications of Altered Stress Hormones Following Acute Exercise

Endocrines ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 121-132
Author(s):  
Erik D. Hanson ◽  
Lauren C. Bates ◽  
Kaileigh Moertl ◽  
Elizabeth S. Evans
Keyword(s):  
Prostate Cancer ◽  
Immune System ◽  
Cancer Survivors ◽  
Nk Cells ◽  
Natural Killer ◽  
Acute Exercise ◽  
Nk Cell ◽  
Killer Cell ◽  
Current Evidence ◽  
Cell Mobilization

Natural killer (NK) cells from the innate immune system are integral to overall immunity and also in managing the tumor burden during cancer. Breast (BCa) and prostate cancer (PCa) are the most common tumors in U.S. adults. Both BCa and PCa are frequently treated with hormone suppression therapies that are associated with numerous adverse effects including direct effects on the immune system. Regular exercise is recommended for cancer survivors to reduce side effects and improve quality of life. Acute exercise is a potent stimulus for NK cells in healthy individuals with current evidence indicating that NK mobilization in individuals with BCa and PCa is comparable. NK cell mobilization results from elevations in shear stress and catecholamine levels. Despite a normal NK cell response to exercise, increases in epinephrine are attenuated in BCa and PCa. The significance of this potential discrepancy still needs to be determined. However, alterations in adrenal hormone signaling are hypothesized to be due to chronic stress during cancer treatment. Additional compensatory factors induced by exercise are reviewed along with recommendations on standardized approaches to be used in exercise immunology studies involving oncology populations.

scholarly journals Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment

2010 ◽  
Vol 207 (10) ◽  
pp. 2065-2072 ◽  
Author(s):  
Nathalie T. Joncker ◽  
Nataliya Shifrin ◽  
Frédéric Delebecque ◽  
David H. Raulet
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Wild Type ◽  
Mhc I ◽  
Cell Functions ◽  
Histocompatibility Complex ◽  
Activating Receptors ◽  
Nk Cell Differentiation ◽  
Deficient Mice

Some mature natural killer (NK) cells cannot be inhibited by major histocompatibility complex (MHC) I molecules, either because they lack corresponding inhibitory receptors or because the host lacks the corresponding MHC I ligands for the receptors. Such NK cells nevertheless remain self-tolerant and exhibit a generalized hyporesponsiveness to stimulation through activating receptors. To address whether NK cell responsiveness is set only during the NK cell differentiation process, we transferred mature NK cells from wild-type (WT) to MHC I–deficient hosts or vice versa. Remarkably, mature responsive NK cells from WT mice became hyporesponsive after transfer to MHC I–deficient mice, whereas mature hyporesponsive NK cells from MHC I–deficient mice became responsive after transfer to WT mice. Altered responsiveness was evident among mature NK cells that had not divided in the recipient animals, indicating that the cells were mature before transfer and that alterations in activity did not require cell division. Furthermore, the percentages of NK cells expressing KLRG1, CD11b, CD27, and Ly49 receptors specific for H-2b were not markedly altered after transfer. Thus, the functional activity of mature NK cells can be reset when the cells are exposed to a changed MHC environment. These findings have important implications for how NK cell functions may be curtailed or enhanced in the context of disease.

scholarly journals TIM-3 Expression Is Downregulated on Human NK Cells in Response to Cancer Targets in Synergy with Activation

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2417 ◽  
Author(s):  
Tram N. Dao ◽  
Sagar Utturkar ◽  
Nadia Atallah Lanman ◽  
Sandro Matosevic
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Interferon Gamma ◽  
Nk Cell ◽  
Ex Vivo ◽  
Cell Dysfunction ◽  
Nk Cell Receptors ◽  
Ifn Γ

Among natural killer (NK) cell receptors, the T-cell immunoglobulin and mucin-containing domain (TIM-3) has been associated with both inhibitory and activating functions, depending on context and activation pathway. Ex vivo and in vitro, expression of TIM-3 is inducible and depends on activation stimulus. Here, we report that TIM-3 expression can be downregulated on NK cells under specific conditions. When NK cells are exposed to cancer targets, they synergize with stimulation conditions to induce a substantial decrease in TIM-3 expression on their surface. We found that such downregulation occurs following prior NK activation. Downregulated TIM-3 expression correlated to lower cytotoxicity and lower interferon gamma (IFN-γ) expression, fueling the notion that TIM-3 might function as a benchmark for human NK cell dysfunction.

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