Abstract 3767: Imprime PGG, a soluble yeast b-glucan PAMP, enhancement of anti-tumor responses in combination with tumor targeting antibody is highly dependent on NK cell killing

Natural killer (NK) cells hold a pivotal role in tumor-targeting monoclonal antibody (mAb)-based activity due to the expression of CD16, the low-affinity receptor for IgG. Indeed, beyond exerting cytotoxic function, activated NK cells also produce an array of cytokines and chemokines, through which they interface with and potentiate adaptive immune responses. Thus, CD16-activated NK cells can concur to mAb-dependent “vaccinal effect”, i.e., the development of antigen-specific responses, which may be highly relevant in maintaining long-term protection of treated patients. On this basis, the review will focus on strategies aimed at potentiating NK cell-mediated antitumor functions in tumor-targeting mAb-based regimens, represented by (a) mAb manipulation strategies, aimed at augmenting recruitment and efficacy of NK cells, such as Fc-engineering, and the design of bi- or trispecific NK cell engagers and (b) the possible exploitation of memory NK cells, whose distinctive characteristics (enhanced responsiveness to CD16 engagement, longevity, and intrinsic resistance to the immunosuppressive microenvironment) may maximize therapeutic mAb antitumor efficacy.

Download Full-text

HkRP3 Is a Microtubule-Binding Protein Regulating Lytic Granule Clustering and NK Cell Killing

The Journal of Immunology ◽

10.4049/jimmunol.1402897 ◽

2015 ◽

Vol 194 (8) ◽

pp. 3984-3996 ◽

Cited By ~ 18

Author(s):

Hyoungjun Ham ◽

Walter Huynh ◽

Renee A. Schoon ◽

Ronald D. Vale ◽

Daniel D. Billadeau

Keyword(s):

Nk Cell ◽

Binding Protein ◽

Cell Killing ◽

Microtubule Binding ◽

Lytic Granule

Download Full-text

SECOND MESSANGER FUNCTION OF LIPOXYGENATION PRO DUCTS IN HUMAN NK CELL KILLING

Pediatric Research ◽

10.1203/00006450-198510000-00129 ◽

1985 ◽

Vol 19 (10) ◽

pp. 1089-1089

Author(s):

Paolo Rossi

Keyword(s):

Nk Cell ◽

Cell Killing

Download Full-text

Studies on the calcium dependence of human NK cell killing

Biochemical Pharmacology ◽

10.1016/0006-2952(87)90462-x ◽

1987 ◽

Vol 36 (22) ◽

pp. 3943-3949 ◽

Cited By ~ 13

Author(s):

Janet Ng ◽

Bertil B. Fredholm ◽

Mikael Jondal

Keyword(s):

Nk Cell ◽

Cell Killing ◽

Calcium Dependence

Download Full-text

IMMU-42. OPTIMIZING IMMUNOTHERAPY FOR GLIOMA USING CYTOKINE-ACTIVATED NATURAL KILLER CELLS

Neuro-Oncology ◽

10.1093/neuonc/noab196.401 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi101-vi102

Author(s):

Amber Kerstetter-Fogle ◽

Folashade Otegbeye ◽

David Soler ◽

Peggy Harris ◽

Alankrita Raghavan ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Glioma Cell ◽

Cell Function ◽

Nk Cell ◽

Cell Killing ◽

Cellular Immunotherapy ◽

Stereotactic Radiation ◽

Tumor Bed

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most common primary central nervous system malignancy associated with a 12-15 month survival after surgery and radio-chemotherapy. Utilizing adoptive cellular immunotherapy using natural killer (NK) cells has developed over the past two decades for a variety of hematologic malignancies. This approach in solid malignancies is limited by questions of cell dose versus tumor burden, insufficient tumor infiltration, and a tumor microenvironment that suppresses NK cell function. METHODS We isolated NK cells from healthy volunteers and activated them using IL-2, -15, -12, -18, then perform cytotoxic assays in the presence of glioma stem cells. We also tested the efficacy of the NK cells with intracranial delivery in a pre-clinical murine model of glioma. We tested various concentrations of IL-2 and IL-15 on the cytokine culture platform. RESULTS In this study, we demonstrate human NK cells, activated using a cytokine cocktail of interleukins-2, -15, -12, and -18, exert strong cytotoxic events against glioma cell lines. To further examine the efficacy of activated NK cells in vitro, we utilized intracranially xenografted glioma lines and demonstrated a survival benefit with tumor bed injections of these cytokine-activated NK cells (p=0.0089). We were able to confirm that NK cells cultured with low doses (200u IL2; 50ng/ml IL15) of both cytokines are just as effective as higher doses. This is important, as in vivoexhaustion of NK cells stimulated with high doses of either cytokine has been well validated. We also found that low-dose irradiation (4Gy) of glioma cells prior to co-culture with cytokine-activated NK cells promoted increased targeted glioma cell killing within 4 hours(32% cell killing). CONCLUSIONS These findings suggest that in a clinical study, injection of cytokine-activated NK cells into the glioblastoma tumor bed could be used as adjuvant treatment following either stereotactic radiation or surgical resection.

Download Full-text

Enhancing network activation in natural killer cells: predictions from in silico modeling

Integrative Biology ◽

10.1093/intbio/zyaa008 ◽

2020 ◽

Vol 12 (5) ◽

pp. 109-121

Author(s):

Sahak Z Makaryan ◽

Stacey D Finley

Keyword(s):

Nk Cells ◽

Natural Killer ◽

In Silico ◽

Intracellular Signaling ◽

Cell Activation ◽

Nk Cell ◽

Mechanistic Model ◽

Cell Killing ◽

Published Data ◽

Network Activation

Abstract Natural killer (NK) cells are part of the innate immune system and are capable of killing diseased cells. As a result, NK cells are being used for adoptive cell therapies for cancer patients. The activation of NK cell stimulatory receptors leads to a cascade of intracellular phosphorylation reactions, which activates key signaling species that facilitate the secretion of cytolytic molecules required for cell killing. Strategies that maximize the activation of such intracellular species can increase the likelihood of NK cell killing upon contact with a cancer cell and thereby improve efficacy of NK cell-based therapies. However, due to the complexity of intracellular signaling, it is difficult to deduce a priori which strategies can enhance species activation. Therefore, we constructed a mechanistic model of the CD16, 2B4 and NKG2D signaling pathways in NK cells to simulate strategies that enhance signaling. The model predictions were fit to published data and validated with a separate dataset. Model simulations demonstrate strong network activation when the CD16 pathway is stimulated. The magnitude of species activation is most sensitive to the receptor’s initial concentration and the rate at which the receptor is activated. Co-stimulation of CD16 and NKG2D in silico required fewer ligands to achieve half-maximal activation than other combinations, suggesting co-stimulating these pathways is most effective in activating the species. We applied the model to predict the effects of perturbing the signaling network and found two strategies that can potently enhance network activation. When the availability of ligands is low, it is more influential to engineer NK cell receptors that are resistant to proteolytic cleavage. In contrast, for high ligand concentrations, inhibiting phosphatase activity leads to sustained species activation. The work presented here establishes a framework for understanding the complex, nonlinear aspects of NK cell signaling and provides detailed strategies for enhancing NK cell activation.

Download Full-text