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.

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.

scholarly journals HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1207-1214 ◽  
Author(s):  
Jeffrey Ward ◽  
Matthew Bonaparte ◽  
Jennifer Sacks ◽  
Jacqueline Guterman ◽  
Manuela Fogli ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Target Cells ◽  
Nk Cell Receptors ◽  
Infected Cells ◽  
Cytotoxic Responses

AbstractThe ability of natural killer (NK) cells to kill virus-infected cells depends on the presence of ligands for activation receptors on the target cells. We found the presence of few, if any, NKp30 and NK46 ligands on T cell blasts infected with HIV, although NKp44 ligands were found on infected cells. HIV does induce the NKG2D ligands ULBP-1, -2, and -3. These ligands are involved in triggering NK cells to kill autologous HIV-infected cells, because interfering with the interaction between NKG2D, but not NKp46, on NK cells and its ligands on HIV-infected cells drastically reduced the lysis of infected cells. Interfering with the binding of the NK-cell coreceptors NTB-A and 2B4 to their ligands also decreased destruction by NK cells. The coreceptor ligands, NTB-A and CD48, were also found to be down-regulated during the course of HIV infection. Thus, ligands for NK-cell receptors are modulated during the course of HIV infection, which may greatly alter NK cells' ability to kill the infected cells.

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.

scholarly journals Molecular Signatures of Natural Killer Cells in CMV-Associated Anterior Uveitis, A New Type of CMV-Induced Disease in Immunocompetent Individuals

2021 ◽  
Vol 22 (7) ◽  
pp. 3623
Author(s):  
Nobuyo Yawata ◽  
Mariko Shirane ◽  
Kaing Woon ◽  
Xinru Lim ◽  
Hidenori Tanaka ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Anterior Uveitis ◽  
Genetic Background ◽  
Nk Cell ◽  
Hla Class I ◽  
Class I ◽  
Molecular Signatures ◽  
Receptor Ligand ◽  
Ligand Interactions

Cytomegalovirus (CMV) causes clinical issues primarily in immune-suppressed conditions. CMV-associated anterior uveitis (CMV-AU) is a notable new disease entity manifesting recurrent ocular inflammation in immunocompetent individuals. As patient demographics indicated contributions from genetic background and immunosenescence as possible underlying pathological mechanisms, we analyzed the immunogenetics of the cohort in conjunction with cell phenotypes to identify molecular signatures of CMV-AU. Among the immune cell types, natural killer (NK) cells are main responders against CMV. Therefore, we first characterized variants of polymorphic genes that encode differences in CMV-related human NK cell responses (Killer cell Immunoglobulin-like Receptors (KIR) and HLA class I) in 122 CMV-AU patients. The cases were then stratified according to their genetic features and NK cells were analyzed for human CMV-related markers (CD57, KLRG1, NKG2C) by flow cytometry. KIR3DL1 and HLA class I combinations encoding strong receptor–ligand interactions were present at substantially higher frequencies in CMV-AU. In these cases, NK cell profiling revealed expansion of the subset co-expressing CD57 and KLRG1, and together with KIR3DL1 and the CMV-recognizing NKG2C receptor. The findings imply that a mechanism of CMV-AU pathogenesis likely involves CMV-responding NK cells co-expressing CD57/KLRG1/NKG2C that develop on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor–ligand interactions.

scholarly journals Neutrophils Induced Licensing of Natural Killer Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Keishiro Amano ◽  
Masahiro Hirayama ◽  
Eiichi Azuma ◽  
Shotaro Iwamoto ◽  
Yoshitaka Keida ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Peripheral Blood Mononuclear ◽  
Ligand Interaction ◽  
Receptor Ligand ◽  
Hematopoietic Stem ◽  
Nk Receptor

Natural killer (NK) cells acquire effector function through a licensing process and exert anti-leukemia/tumor effect. However, there is no means to promote a licensing effect of allogeneic NK cells other than cytomegalovirus reactivation-induced licensing in allogeneic hematopoietic stem cell transplantation in human. In mice, a licensing process is mediated by Ly49 receptors which recognize self-major histocompatibility complex class I. The distribution of four Ly49 receptors showed similar pattern in congenic mice, B10, B10.BR, and B10.D2, which have B10 background. Forty Gy-irradiated2×106B10.D2 cells including splenocytes, peripheral blood mononuclear cells in untreated mice, or granulocyte colony-stimulating factor treated mice were injected intraperitoneally into B10 mice. We found that murine NK cells were effectively licensed by intraperitoneal injection of donor neutrophils with its corresponding NK receptor ligand in B10 mice as a recipient and B10.D2 as a donor. Mechanistic studies revealed that NK cells showed the upregulation of intracellular interferon-γand CD107a expression as markers of NK cell activation. Moreover, enriched neutrophils enhanced licensing effect of NK cells; meanwhile, licensing effect was diminished by depletion of neutrophils. Collectively, injection of neutrophils induced NK cell licensing (activation) via NK receptor ligand interaction.

scholarly journals The m15 Locus of Murine Cytomegalovirus Modulates Natural Killer Cell Responses to Promote Dissemination to the Salivary Glands and Viral Shedding

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 866
Author(s):  
Baca Chan ◽  
Maja Arapović ◽  
Laura Masters ◽  
Francois Rwandamuiye ◽  
Stipan Jonjić ◽  
...  
Keyword(s):  
Nk Cells ◽  
Salivary Glands ◽  
Natural Killer ◽  
Nk Cell ◽  
Acute Infection ◽  
Killer Cell ◽  
Viral Escape ◽  
Murine Cytomegalovirus ◽  
Viral Shedding ◽  
Cell Responses

As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as a viral modulator of natural killer (NK) cell immunity. We show that, rather than discrete transcripts from the m14, m15 and m16 genes as annotated, there are five 3′-coterminal transcripts expressed over this region, all utilising a consensus polyA tail at the end of the m16 gene. Functional inactivation of any one of these genes had no measurable impact on viral replication. However, disruption of all five transcripts led to significantly attenuated dissemination to, and replication in, the salivary glands of multiple strains of mice, but normal growth during acute infection. Disruption of the m15 locus was associated with heightened NK cell responses, including enhanced proliferation and IFNγ production. Depletion of NK cells, but not T cells, rescued salivary gland replication and viral shedding. These data demonstrate the identification of multiple transcripts expressed by a single locus which modulate, perhaps in a concerted fashion, the function of anti-viral NK cells.

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 Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2796
Author(s):  
Aicha E. Quamine ◽  
Mallery R. Olsen ◽  
Monica M. Cho ◽  
Christian M. Capitini
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Nk Cell ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Intensive Therapy ◽  
Killer Cell ◽  
Cell Therapies ◽  
Pediatric Solid Tumors

Treatment of metastatic pediatric solid tumors remain a significant challenge, particularly in relapsed and refractory settings. Standard treatment has included surgical resection, radiation, chemotherapy, and, in the case of neuroblastoma, immunotherapy. Despite such intensive therapy, cancer recurrence is common, and most tumors become refractory to prior therapy, leaving patients with few conventional treatment options. Natural killer (NK) cells are non-major histocompatibility complex (MHC)-restricted lymphocytes that boast several complex killing mechanisms but at an added advantage of not causing graft-versus-host disease, making use of allogeneic NK cells a potential therapeutic option. On top of their killing capacity, NK cells also produce several cytokines and growth factors that act as key regulators of the adaptive immune system, positioning themselves as ideal effector cells for stimulating heavily pretreated immune systems. Despite this promise, clinical efficacy of adoptive NK cell therapy to date has been inconsistent, prompting a detailed understanding of the biological pathways within NK cells that can be leveraged to develop “next generation” NK cell therapies. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors.

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 Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hee Young Na ◽  
Yujun Park ◽  
Soo Kyung Nam ◽  
Jiwon Koh ◽  
Yoonjin Kwak ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Prognostic Significance

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.

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