scholarly journals Molecular Scale Spatio-Chemical Control of the Activating-Inhibitory Signal Integration in NK Cells

2020 ◽  
Author(s):  
Esti Toledo ◽  
Guillaume Le Saux ◽  
Long Li ◽  
Maor Rosenberg ◽  
Yossi Keidar ◽  
...  
Keyword(s):  
Nk Cells ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Spatial Interaction ◽  
Immune Checkpoints ◽  
Cytotoxic Lymphocytes ◽  
Inhibitory Receptors ◽  
Molecular Scale ◽  
Cell Niche

AbstractThe role of the spatial juxtaposition between activating and inhibitory receptors in cytotoxic lymphocytes has been strongly debated in the context of the inhibition of immune signaling. The challenge in addressing this problem was so far a lack of experimental tools which can simultaneously manipulate different signaling molecules. Here, we circumvent this challenge by introducing a nanoengineered multifunctional cell niche, in which activating and inhibitory ligands are positioned with molecular-scale variability and control, and applied it to elucidate the role of the spatial juxtaposition between ligands for NKG2D and KIR2DL1 – activating and inhibitory receptors in Natural Killer (NK) cells – in KIR2DL1-mediated inhibition of NKG2D signaling. We realized the niche by a nanopatterning of nanodots of different metals with molecular scale registry in one lithographic step, followed by a novel ternary functionalization of the fabricated bi-metallic pattern and its background to with three distinct biochemical moieties. We found, that within the probed range, the 40 nm gap between the activating and inhibitory ligands provided an optimal inhibition condition. Supported by theoretical modeling and simulations we interpret these findings as a consequence of the size and conformational flexibility of the ligands in their spatial interaction. Our findings provide an important insight onto the spatial mechanism of the inhibitory immune checkpoints, whose understanding is both fundamentally important, and essential for the rational design of future immunotherapies. Furthermore, our approach is highly versatile and paves the way to numerous complex molecular platforms aimed at revealing molecular mechanisms through which receptors integrate their signals.

scholarly journals Molecular-scale spatio-chemical control of the activating-inhibitory signal integration in NK cells

2021 ◽  
Vol 7 (24) ◽  
pp. eabc1640
Author(s):  
Esti Toledo ◽  
Guillaume Le Saux ◽  
Avishay Edri ◽  
Long Li ◽  
Maor Rosenberg ◽  
...  
Keyword(s):  
Rational Design ◽  
Spatial Interaction ◽  
Immune Checkpoints ◽  
Cytotoxic Lymphocytes ◽  
Signal Integration ◽  
Size Mismatch ◽  
Molecular Scale ◽  
Signaling Receptors ◽  
Insight Into

The role of juxtaposition of activating and inhibitory receptors in signal inhibition of cytotoxic lymphocytes remains strongly debated. The challenge lies in the lack of tools that allow simultaneous spatial manipulation of signaling molecules. To circumvent this, we produced a nanoengineered multifunctional platform with molecular-scale spatial control of ligands, which was applied to elucidate KIR2DL1-mediated inhibition of NKG2D signaling—receptors of natural killer cells. This platform was conceived by bimetallic nanodot patterning with molecular-scale registry, followed by a ternary functionalization with distinct moieties. We found that a 40-nm gap between activating and inhibitory ligands provided optimal inhibitory conditions. Supported by theoretical modeling, we interpret these findings as a consequence of the size mismatch and conformational flexibility of ligands in their spatial interaction. This highly versatile approach provides an important insight into the spatial mechanism of inhibitory immune checkpoints, which is essential for the rational design of future immunotherapies.

scholarly journals Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion

2021 ◽  
Vol 7 (8) ◽  
pp. eabc2331 ◽  
Author(s):  
Jose M. Ayuso ◽  
Shujah Rehman ◽  
Maria Virumbrales-Munoz ◽  
Patrick H. McMinn ◽  
Peter Geiger ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Waste Product ◽  
Extended Period ◽  
Cell Exhaustion

Solid tumors generate a suppressive environment that imposes an overwhelming burden on the immune system. Nutrient depletion, waste product accumulation, hypoxia, and pH acidification severely compromise the capacity of effector immune cells such as T and natural killer (NK) cells to destroy cancer cells. However, the specific molecular mechanisms driving immune suppression, as well as the capacity of immune cells to adapt to the suppressive environment, are not completely understood. Thus, here, we used an in vitro microfluidic tumor-on-a-chip platform to evaluate how NK cells respond to the tumor-induced suppressive environment. The results demonstrated that the suppressive environment created by the tumor gradually eroded NK cell cytotoxic capacity, leading to compromised NK cell surveillance and tumor tolerance. Further, NK cell exhaustion persisted for an extended period of time after removing NK cells from the microfluidic platform. Last, the addition of checkpoint inhibitors and immunomodulatory agents alleviated NK cell exhaustion.

Aberrant protein glycosylation in cancer: implications in targeted therapy

2021 ◽  
Author(s):  
Joana G. Rodrigues ◽  
Henrique O. Duarte ◽  
Celso A. Reis ◽  
Joana Gomes
Keyword(s):  
Targeted Therapy ◽  
Tumour Cell ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Clinical Performance ◽  
Therapeutic Strategies ◽  
Protein Glycosylation ◽  
Immune Checkpoints ◽  
Immunosuppressive Microenvironment ◽  
The Impact

Aberrant cell surface glycosylation signatures are currently known to actively drive the neoplastic transformation of healthy cells. By disrupting the homeostatic functions of their protein carriers, cancer-associated glycans mechanistically underpin several molecular hallmarks of human malignancy. Furthermore, such aberrant glycan structures play key roles in the acquisition of molecular resistance to targeted therapeutic agents, which compromises their clinical efficacy, by modulating tumour cell aggressiveness and supporting the establishment of an immunosuppressive microenvironment. Recent advances in the study of the tumour cell glycoproteome have unravelled previously elusive molecular mechanisms of therapeutic resistance, guided the rational design of novel personalized therapeutic strategies, and may further improve the clinical performance of currently approved anti-cancer targeted agents. In this review, we highlight the impact of glycosylation in cancer targeted therapy, with particular focus on receptor tyrosine kinase-targeted therapy, immune checkpoints blockade therapy, and current developments on therapeutic strategies directed to glycan-binding proteins and other innovative glycan therapeutic strategies.

scholarly journals Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Yuqing Cao ◽  
Xiaoyu Wang ◽  
Tianqiang Jin ◽  
Yu Tian ◽  
Chaoliu Dai ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Immune Checkpoint ◽  
Therapeutic Target ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Immune Checkpoints ◽  
Immune Checkpoint Molecules

Abstract Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

scholarly journals Nonstochastic Coexpression of Activation Receptors on Murine Natural Killer Cells

2000 ◽  
Vol 191 (8) ◽  
pp. 1341-1354 ◽  
Author(s):  
Hamish R.C. Smith ◽  
Hubert H. Chuang ◽  
Lawrence L. Wang ◽  
Margarita Salcedo ◽  
Jonathan W. Heusel ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Inhibitory Receptors ◽  
Antigen Receptors ◽  
Killer Cells ◽  
Histocompatibility Complex ◽  
Nk Cell Cytotoxicity

Murine natural killer cells (NK) express lectin-like activation and inhibitory receptors, including the CD94/NKG2 family of receptors that bind Qa-1, and the Ly-49 family that recognizes major histocompatibility complex class I molecules. Here, we demonstrate that cross-linking of NK cells with a new specific anti–Ly-49H mAb induced NK cell cytotoxicity and cytokine production. Ly-49H is expressed on a subset of NK cells and can be coexpressed with Ly-49 inhibitory receptors. However, unlike Ly-49 inhibitory receptors, Ly-49H is not detectable on naive splenic CD3+ T cells, indicating that Ly-49H may be an NK cell–specific activation receptor. In further contrast to the stochastically expressed Ly-49 inhibitory receptors, Ly-49H is preferentially expressed with the Ly-49D activation receptor, and expression of both Ly-49H and Ly-49D is augmented on NK cells that lack receptors for Qa-1 tetramers. On developing splenic NK1.1+ cells, Ly-49D and Ly-49H are expressed later than the inhibitory receptors. These results directly demonstrate that Ly-49H activates primary NK cells, and suggest that expression of Ly-49 activation receptors by NK cells may be specifically regulated on NK cell subsets. The simultaneous expression of multiple activation receptors by individual NK cells contrasts with that of T cell antigen receptors and is relevant to the role of NK cells in innate immunity.

scholarly journals NF-kB c-Rel is dispensable for the development but is required for the cytotoxic function of NK cells

2021 ◽  
Author(s):  
Y Vicioso ◽  
K Zhang ◽  
Parameswaran Ramakrishnan ◽  
Reshmi Parameswaran
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Granzyme B ◽  
Conditional Knockout ◽  
Cytotoxic Lymphocytes ◽  
And Control ◽  
Cytotoxic Function

AbstractNatural Killer (NK) cells are cytotoxic lymphocytes critical to the innate immune system. We found that germline deficiency of NF-kB c-Rel results in a marked decrease in cytotoxic function of NK cells, both in vitro and in vivo, with no significant differences in the stages of NK cell development. We found that c-Rel binds to the promoters of perforin and granzyme B, two key proteins required for NK cytotoxicity, and controls their transactivation. We generated a NK cell specific c-Rel conditional knockout to study NK cell intrinsic role of c-Rel and found that both global and conditional c-Rel deficiency leads to decreased perforin and granzyme B expression and thereby cytotoxic function. We also confirmed the role of c-Rel in perforin and granzyme B expression in human NK cells. c-Rel reconstitution rescued perforin and granzyme B expressions in c-Rel deficient NK cells and restored their cytotoxic function. Our results show a previously unknown role of c-Rel in transcriptional regulation of perforin and granzyme B expressions and control of NK cell cytotoxic function.

scholarly journals Hlx homeobox transcription factor negatively regulates interferon-γ production in monokine-activated natural killer cells

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2481-2487 ◽  
Author(s):  
Brian Becknell ◽  
Tiffany L. Hughes ◽  
Aharon G. Freud ◽  
Bradley W. Blaser ◽  
Jianhua Yu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nk Cells ◽  
Natural Killer ◽  
Molecular Mechanisms ◽  
Interferon Γ ◽  
Tumor Surveillance ◽  
Protein Levels ◽  
Homeobox Transcription Factor ◽  
Ifn Γ

Abstract Natural killer (NK) cells contribute to host immunity, including tumor surveillance, through the production of interferon gamma (IFN-γ). Although there is some knowledge about molecular mechanisms that induce IFN-γ in NK cells, considerably less is known about the mechanisms that reduce its expression. Here, we investigate the role of the Hlx transcription factor in IFN-γ production by NK cells. Hlx expression is induced in monokine-activated NK cells, but with delayed kinetics compared to IFN-γ. Ectopic Hlx expression decreases IFN-γ synthesis in primary human NK cells and IFN-γ promoter activity in an NK-like cell line. Hlx protein levels inversely correlate with those of STAT4, a requisite factor for optimal IFN-γ transcription. Mechanistically, we provide evidence indicating that Hlx overexpression accelerates dephosphorylation and proteasome-dependent degradation of the active Y693-phosphorylated form of STAT4. Thus, Hlx expression in activated NK cells temporally controls and limits the monokine-induced production of IFN-γ, in part through the targeted depletion of STAT4.

scholarly journals Role of KIR Receptor in NK Regulation during Viral Infections

Immuno ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 305-331
Author(s):  
Sabrina Rizzo ◽  
Giovanna Schiuma ◽  
Silvia Beltrami ◽  
Valentina Gentili ◽  
Roberta Rizzo ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Cell Activation ◽  
Viral Infections ◽  
Nk Cell ◽  
Human Leukocyte ◽  
Target Cells ◽  
Inhibitory Receptors ◽  
Receptor Repertoire

Natural Killer (NK) cells are key effectors of the innate immune system which represent the first line of defense against viral infections. NK cell activation depends on the engagement of a complex receptor repertoire expressed on their surface, consisting of both activating and inhibitory receptors. Among the known NK cell receptors, the family of killer Ig-like receptors (KIRs) consists in activating/inhibitory receptors that interact with specific human leukocyte antigen (HLA) molecules expressed on target cells. In particular, the expression of peculiar KIRs have been reported to be associated to viral infection susceptibility. Interestingly, a significant association between the development and onset of different human pathologies, such as tumors, neurodegeneration and infertility, and a clonal KIRs expression on NK cells has been described in presence of viral infections, supporting the crucial role of KIRs in defining the effect of viral infections in different tissues and organs. This review aims to report the state of art about the role of KIRs receptors in NK cell activation and viral infection control.

The role of oxidative stress in NK-cell based cancer immunotherapy

2019 ◽  
Vol 6 ◽  
pp. 33-42
Author(s):  
Marta Kłopotowska ◽  
Magdalena Winiarska
Keyword(s):  
Oxidative Stress ◽  
Cancer Treatment ◽  
Nk Cells ◽  
Nk Cell ◽  
Adoptive Cell Therapy ◽  
Cell Activity ◽  
Cytotoxic Lymphocytes ◽  
Antigen Receptors ◽  
Tumor Environment

Immunooncology gained great attention in cancer treatment over the last few years. Adoptive cell therapy is a type of immunotherapy that uses cytotoxic lymphocytes or NK cells. NK cells precisely recognize and kill cancer cells without affecting healthy cells. These properties make NK cells an attractive strategy with potential therapeutic applications. NK cells can be further modified with chimeric antigen receptors (CAR). Currently, several dozen clinical trials with NK cells are registered for cancer treatment, including several CAR-NK cells or NK-92 cell line modified with CAR. Despite the undeniable success of immunotherapy in recent years, many concerns still remain unresolved. One of the challenges for the effective immunotherapy is the immunosuppressive tumor environment. Numerous studies indicate that persistent oxidative stress, an important element associated with cancer, inhibits NK cell activity. However, the exact mechanisms responsible for protecting NK cells against suppressive oxidative stress are not identified. Therefore, in my doctoral dissertation co-financed by the Scientific Polpharma Foundation doctoral scholarship I focused on investigating and identifying mechanisms protecting NK cells against oxidative stress. The obtained results indicate that NK cells are the most sensitive to the oxidative stress, when compared withother immune cells. Moreover, inhibition of PRDX1-TXN1-TXNRD1 system impairs NK cell effector functions, while the increase of PRDX1 significantly improves the survival of NK cells and CAR-NK cells in the presence of H<sub>2</sub>O<sub>2</sub>, resulting in improved effectiveness of NK cells under the oxidative stress conditions.

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