scholarly journals A universal CAR-NK cell approach for HIV eradication

2021 ◽  
Vol 5 (3) ◽  
pp. 192-194
Author(s):  
Arosh S. Perera Molligoda Arachchige ◽  
Keyword(s):  
Drug Development ◽  
Hiv Infection ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Nk Cell ◽  
Therapeutic Drug ◽  
Effective Solution ◽  
Hiv Eradication ◽  
Novel Approaches ◽  
The Way

<abstract> <p>No therapeutic drug has been able to completely eradicate HIV-infection so far, even after decades of research. A major challenge in HIV drug development is its immense diversity. NK cells are well-known for their anti-viral and anti-tumor functions. Since recently, NK cells have gained interest of researchers as they have paved the way for novel approaches in controlling HIV-infection supported by promising results observed in cancer immunotherapy trials. Here we report an anti-DNP CAR-NK cell approach introduced by Lim et al. capable of recognizing 2,4-dinitrophenyl tagged to anti-gp160 antibodies, which seemingly provides an effective solution to counteract HIV variability.</p> </abstract>

scholarly journals Interleukin-15-Stimulated Natural Killer Cells Clear HIV-1-Infected Cells following Latency ReversalEx Vivo

2018 ◽  
Vol 92 (12) ◽  
pp. e00235-18 ◽  
Author(s):  
Carolina Garrido ◽  
Maria Abad-Fernandez ◽  
Marina Tuyishime ◽  
Justin J. Pollara ◽  
Guido Ferrari ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Receptor Expression ◽  
Immune Recognition ◽  
Hiv Eradication ◽  
Infected Cells ◽  
Interleukin 15 ◽  
The Impact

ABSTRACTCurrent efforts toward human immunodeficiency virus (HIV) eradication include approaches to augment immune recognition and elimination of persistently infected cells following latency reversal. Natural killer (NK) cells, the main effectors of the innate immune system, recognize and clear targets using different mechanisms than CD8+T cells, offering an alternative or complementary approach for HIV clearance strategies. We assessed the impact of interleukin 15 (IL-15) treatment on NK cell function and the potential for stimulated NK cells to clear the HIV reservoir. We measured NK cell receptor expression, antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxicity, interferon gamma (IFN-γ) production, and antiviral activity in autologous HIV replication systems. All NK cell functions were uniformly improved by IL-15, and, more importantly, IL-15-treated NK cells were able to clear latently HIV-infected cells after exposure to vorinostat, a clinically relevant latency-reversing agent. We also demonstrate that NK cells from HIV-infected individuals aviremic on antiretroviral therapy can be efficiently stimulated with IL-15. Our work opens a promising line of investigation leading to future immunotherapies to clear persistent HIV infection using NK cells.IMPORTANCEIn the search for an HIV cure, strategies to enhance immune function to allow recognition and clearance of HIV-infected cells following latency reversal are being evaluated. Natural killer (NK) cells possess characteristics that can be exploited for immunotherapy against persistent HIV infection. We demonstrate that NK cells from HIV-positive donors can be strongly stimulated with IL-15, improving their antiviral and cytotoxic potential and, more importantly, clearing HIV-infected cells after latency reversal with a clinically relevant drug. Our results encourage further investigation to design NK cell-based immunotherapies to achieve HIV eradication.

scholarly journals The Advances and Challenges of NK Cell-Based Cancer Immunotherapy

2021 ◽  
Vol 28 (2) ◽  
pp. 1077-1093
Author(s):  
Synat Kang ◽  
Xuefeng Gao ◽  
Li Zhang ◽  
Erna Yang ◽  
Yonghui Li ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Nk Cell ◽  
Tumor Development ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Clinical Applications ◽  
Therapeutic Approaches ◽  
Leukocyte Antigens ◽  
Recognition Specificity

Natural killer (NK) cells can be widely applied for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization or human leukocyte antigens-matching. Several NK-based therapeutic approaches have been attempted in clinical practice, but their efficacy is not sufficient to suppress tumor development mainly because of lacking specificity. To this end, the engineering of NK cells with T cell receptor along with CD3 subunits (TCR-NK) has been developed to increase the reactivity and recognition specificity of NK cells toward tumor cells. Here, we review recent advances in redirecting NK cells for cancer immunotherapy and discuss the major challenges and future explorations for their clinical applications.

scholarly journals Recent Advances to Augment NK Cell Cancer Immunotherapy Using Nanoparticles

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 525
Author(s):  
Kwang-Soo Kim ◽  
Dong-Hwan Kim ◽  
Dong-Hyun Kim
Keyword(s):  
Clinical Trials ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Therapeutic Efficacy ◽  
Nk Cell ◽  
Cell Cancer ◽  
Immune Surveillance ◽  
Cytolytic Activity ◽  
Contact Frequency

Among various immunotherapies, natural killer (NK) cell cancer immunotherapy using adoptive transfer of NK cells takes a unique position by targeting tumor cells that evade the host immune surveillance. As the first-line innate effector cell, it has been revealed that NK cells have distinct mechanisms to both eliminate cancer cells directly and amplify the anticancer immune system. Over the last 40 years, NK cell cancer immunotherapy has shown encouraging reports in pre-clinic and clinic settings. In total, 288 clinical trials are investigating various NK cell immunotherapies to treat hematologic and solid malignancies in 2021. However, the clinical outcomes are unsatisfying, with remained challenges. The major limitation is attributed to the immune-suppressive tumor microenvironment (TME), low activity of NK cells, inadequate homing of NK cells, and limited contact frequency of NK cells with tumor cells. Innovative strategies to promote the cytolytic activity, durable persistence, activation, and tumor-infiltration of NK cells are required to advance NK cell cancer immunotherapy. As maturing nanotechnology and nanomedicine for clinical applications, there is a greater opportunity to augment NK cell therapeutic efficacy for the treatment of cancers. Active molecules/cytokine delivery, imaging, and physicochemical properties of nanoparticles are well equipped to overcome the challenges of NK cell cancer immunotherapy. Here, we discuss recent clinical trials of NK cell cancer immunotherapy, NK cell cancer immunotherapy challenges, and advances of nanoparticle-mediated NK cell therapeutic efficacy augmentation.

scholarly journals Soluble and Exosome-Bound α-Galactosylceramide Mediate Preferential Proliferation of Educated NK Cells with Increased Anti-Tumor Capacity

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 298
Author(s):  
Arnika K. Wagner ◽  
Ulf Gehrmann ◽  
Stefanie Hiltbrunner ◽  
Valentina Carannante ◽  
Thuy T. Luu ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Nk Cell ◽  
Mouse Strains ◽  
Target Cells ◽  
Class I Mhc ◽  
Mhc I ◽  
Cell Responses ◽  
Missing Self

Natural killer (NK) cells can kill target cells via the recognition of stress molecules and down-regulation of major histocompatibility complex class I (MHC-I). Some NK cells are educated to recognize and kill cells that have lost their MHC-I expression, e.g., tumor or virus-infected cells. A desired property of cancer immunotherapy is, therefore, to activate educated NK cells during anti-tumor responses in vivo. We here analyze NK cell responses to α-galactosylceramide (αGC), a potent activator of invariant NKT (iNKT) cells, or to exosomes loaded with αGC. In mouse strains which express different MHC-I alleles using an extended NK cell flow cytometry panel, we show that αGC induces a biased NK cell proliferation of educated NK cells. Importantly, iNKT cell-induced activation of NK cells selectively increased in vivo missing self-responses, leading to more effective rejection of tumor cells. Exosomes from antigen-presenting cells are attractive anti-cancer therapy tools as they may induce both innate and adaptive immune responses, thereby addressing the hurdle of tumor heterogeneity. Adding αGC to antigen-loaded dendritic-cell-derived exosomes also led to an increase in missing self-responses in addition to boosted T and B cell responses. This study manifests αGC as an attractive adjuvant in cancer immunotherapy, as it increases the functional capacity of educated NK cells and enhances the innate, missing self-based antitumor response.

scholarly journals HLA-E Up-Regulation Induced by HIV Infection May Directly Contribute to CD94-Mediated Impairment of NK Cells

2005 ◽  
Vol 18 (2) ◽  
pp. 269-276 ◽  
Author(s):  
F. Martini ◽  
C. Agrati ◽  
G. D'Offizi ◽  
F. Poccia
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Treatment Interruption ◽  
Cell Number ◽  
Hiv Replication

Alterations in NK cell numbers and function have been repeatedly shown during HIV infection. In this study, NK cell number and MHC class I expression on CD4+ T cells were studied in HIV patients at different stages of disease progression. An increased expression of HLA-E was seen on CD4+ T cells. In parallel, a reduced number of CD94+ NK cells was observed in advanced disease stages. Moreover, a decline in CD94 expression on NK cells was observed at the HIV replication peak in patients undergoing antiretroviral treatment interruption, suggesting a role of viral replication on NK cells alterations. In vitro HIV infection induced a rapid down-regulation of HLA-A,B,C expression, paralleled by an increased expression of HLA-E surface molecules, the formal ligands of CD94 NK receptors. HIV-infected HLA-E expressing cells were able to inhibit NK cell cytotoxicity through HLA-E expression, since cytotoxicity was restored by antibody masking experiments. These data indicate that the CD94/HLA-E interaction may contribute to NK cell dysfunction in HIV infection, suggesting a role of HIV replication in this process.

scholarly journals Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 753 ◽  
Author(s):  
Loris Zamai ◽  
Genny Del Zotto ◽  
Flavia Buccella ◽  
Sara Gabrielli ◽  
Barbara Canonico ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Response ◽  
Cell Activation ◽  
Nk Cell ◽  
High Sensitivity ◽  
Leukemic Cells ◽  
Target Cells ◽  
Hematopoietic Stem ◽  
Oncologic Patients ◽  
The Way

The NK cell population is characterized by distinct NK cell subsets that respond differently to the various activating stimuli. For this reason, the determination of the optimal cytotoxic activation of the different NK cell subsets can be a crucial aspect to be exploited to counter cancer cells in oncologic patients. To evaluate how the triggering of different combination of activating receptors can affect the cytotoxic responses of different NK cell subsets, we developed a microbead-based degranulation assay. By using this new assay, we were able to detect CD107a+ degranulating NK cells even within the less cytotoxic subsets (i.e., resting CD56bright and unlicensed CD56dim NK cells), thus demonstrating its high sensitivity. Interestingly, signals delivered by the co-engagement of NKp46 with 2B4, but not with CD2 or DNAM-1, strongly cooperate to enhance degranulation on both licensed and unlicensed CD56dim NK cells. Of note, 2B4 is known to bind CD48 hematopoietic antigen, therefore this observation may provide the rationale why CD56dim subset expansion correlates with successful hematopoietic stem cell transplantation mediated by alloreactive NK cells against host T, DC and leukemic cells, while sparing host non-hematopoietic tissues and graft versus host disease. The assay further confirms that activation of LFA-1 on NK cells leads to their granule polarization, even if, in some cases, this also takes to an inhibition of NK cell degranulation, suggesting that LFA-1 engagement by ICAMs on target cells may differently affect NK cell response. Finally, we observed that NK cells undergo a time-dependent spontaneous (cytokine-independent) activation after blood withdrawal, an aspect that may strongly bias the evaluation of the resting NK cell response. Altogether our data may pave the way to develop new NK cell activation and expansion strategies that target the highly cytotoxic CD56dim NK cells and can be feasible and useful for cancer and viral infection treatment.

scholarly journals TLR agonists enhance responsiveness of inflammatory innate immune cells in HLA-B*57-positive HIV patients

2020 ◽  
Vol 99 (1) ◽  
pp. 147-158
Author(s):  
L. Dold ◽  
L. Zimmer ◽  
C. Schwarze-Zander ◽  
C. Boesecke ◽  
R. Mohr ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Nk Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Double Positive ◽  
Hiv Patients ◽  
Ifn Gamma ◽  
Tlr Agonists

Abstract HLA-B*57 affects the course of HIV infection. Under antiretroviral therapy, its effects cannot be explained by outstandingly efficient T cell responses alone but may also involve cells of innate immunity. Studying in vitro stimulation with Pam3CSK4, E. coli LPS-B5 and CpG-ODN-2216, we observed greater induction of IL-6/IL-1beta double-positive CD14+CD16++ monocytes as well as IFN-gamma-positive cytotoxic CD56highCD16neg NK cells in HLA-B*57- versus HLA-B*44-positive HIV patients, while TNF-alpha induction remained unchanged. Differences were not seen in the other monocyte and NK cell subsets or in HLA-matched healthy controls. Our findings show that, in virally suppressed HIV infection, HLA-B*57 is associated with enhanced responsiveness of inflammatory innate immune cells to TLR ligands, possibly contributing to increased vulnerability in sepsis. Key messages • HLA-B*57 is a host factor affecting clinical outcomes of HIV infection. • HLA-B*57 modifies inflammatory subsets of NK cells and monocytes in HIV infection. • In HLA-B*57-positive HIV patients TLR agonists induce enhanced IL-6/IL-1beta in monocytes. • NK cells from HLA-B*57 HIV patients release more IFN-gamma upon TLR costimulation. • HLA-B*57 is linked to enhanced inflammatory responsiveness to TLR ligands.

scholarly journals Cytomegalovirus-Driven Adaption of Natural Killer Cells in NKG2Cnull Human Immunodeficiency Virus-Infected Individuals

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 239 ◽  
Author(s):  
Emilie M. Comeau ◽  
Kayla A. Holder ◽  
Neva J. Fudge ◽  
Michael D. Grant
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Differentiation ◽  
Hiv Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Cytokine Production ◽  
Zinc Finger Protein ◽  
Nk Cell ◽  
Immunodeficiency Virus ◽  
Nk Cell Differentiation

Expansion of natural killer (NK) cells expressing NKG2C occurs following human cytomegalovirus (HCMV) infection and is amplified by human immunodeficiency virus (HIV) co-infection. These NKG2C-expressing NK cells demonstrate enhanced CD16-dependent cytokine production and downregulate FcεRIγ and promyelocytic leukemia zinc finger protein (PLZF). Lacking NKG2C diminishes resistance to HIV infection, but whether this affects NK cell acquisition of superior antibody-dependent function is unclear. Therefore, our objective was to investigate whether HCMV-driven NK cell differentiation is impaired in NKG2Cnull HIV-infected individuals. Phenotypic (CD2, CD16, CD57, NKG2A, FcεRIγ, and PLZF expression) and functional (cytokine induction and cytotoxicity) properties were compared between HIV–infected NKG2Cnull and NKG2C-expressing groups. Cytokine production was compared following stimulation through natural cytotoxicity receptors or through CD16. Cytotoxicity was measured by anti-CD16-redirected lysis and by classical antibody-dependent cell-mediated cytotoxicity (ADCC) against anti-class I human leukocyte antigen (HLA) antibody-coated cells. Our data indicate highly similar HCMV-driven NK cell differentiation in HIV infection with or without NKG2C. While the fraction of mature (CD57pos) NK cells expressing CD2 (p = 0.009) or co-expressing CD2 and CD16 (p = 0.03) was significantly higher in NKG2Cnull HIV-infected individuals, there were no significant differences in NKG2A, FcεRIγ, or PLZF expression. The general phenotypic and functional equivalency observed suggests NKG2C-independent routes of HCMV-driven NK cell differentiation, which may involve increased CD2 expression.

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 Human cytokine-induced memory-like NK cells preserve increased glycolysis but the glycolytic-dependence of their effector functions differ between stimuli

2020 ◽  
Author(s):  
Iñigo Terrén ◽  
Ane Orrantia ◽  
Alba Mosteiro ◽  
Joana Vitallé ◽  
Olatz Zenarruzabeitia ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Nk Cell ◽  
Cellular Functions ◽  
Effector Functions ◽  
Cytokine Stimulation ◽  
Cancer Immunotherapies ◽  
Cell Effector ◽  
Human Cytokine

ABSTRACTNatural Killer (NK) cells acquire memory-like properties following a brief stimulation with IL-12, IL-15 and IL-18. These IL-12/15/18-stimulated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have been revealed as a powerful tool in cancer immunotherapy due to their persistence in the host and their increased effector functions. Several studies have shown that NK cells modulate their metabolism in response to cytokine-stimulation and other stimuli, suggesting that there is a link between metabolism and cellular functions. In this paper, we have analyzed metabolic changes associated to IL-12/15/18-stimulation and the relevance of glycolytic pathway for NK cell effector functions. We have found that CIML NK cells are able to retain increased glycolytic machinery seven days after cytokine withdrawal. Furthermore, we found that glycolytic inhibition with 2-DG is stimuli-dependent and that differently affects to distinct effector functions. These findings may have implications in the design of NK cell-based cancer immunotherapies.

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