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Natural Killer Cells in Cancers
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Natural Killer Cells in Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 68927

Special Issue Editors

Dr. Paola Vacca

E-Mail Website
Guest Editor
Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
Interests: innate immunity; tumor immunology; natural killer cells; innate lymphoid cells; tumor microenvironment; cancer immunotherapy; immunocheckpoints
Special Issues, Collections and Topics in MDPI journals
Dr. Laura Chiossone

E-Mail
Guest Editor
Innate Pharma, Marseille, France
Interests: cancer immunotherapy; tumor immunology; tumor microenvironment; Natural Killer cells; Immune Checkpoints Inhibitors (ICI); monoclonal antibodies

Special Issue Information

Dear Colleagues,

NK cells are key elements of innate immunity, belonging to the innate lymphoid cell (ILC) family. In particular, NK cells mirror the effector function of CD8+ cytotoxic T cells, and thus, these cells are able to mediate powerful anticancer and antiviral responses, directly killing cancer cells and indirectly improving the responses mediated by antibodies and T cells. Importantly, in the tumor microenvironment, the antitumor potential of NK cells could be hindered by interactions occurring between these cells and other immune and/or non-immune cells. Clarifying the characteristics of tumor-infiltrating NK cells and of other ILC subsets, understanding and targeting the interactions occurring in the tumor microenvironment, and improving tumor-immune cell infiltration may help to develop novel protocols of antitumor immunotherapy.

Moreover, since the expression of inhibitory immune checkpoint receptors strongly impairs the NK cell effector function, the definition of the stimuli able to regulate their expression and the mechanisms leading to inactivation/regulation of antitumor NK/ILC activity represent an important goal to design novel therapeutic approaches.

This Special Issue will highlight the diverse roles of NK cells in cancer, covering both basic and clinical aspects that may help to develop strategies targeting these cells in tumors.

Dr. Paola Vacca
Dr. Laura Chiossone
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • natural killer cells
  • innate immunity
  • cancer immunology and immunotherapy
  • tumor microenvironment
  • tumor-infiltrating lymphocytes
  • immune cross-talk

Published Papers (19 papers)

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18 pages, 3145 KiB  
Article
A New Functional Screening Platform Identifies Colistin Sulfate as an Enhancer of Natural Killer Cell Cytotoxicity
by Serena Cortés-Kaplan, Reem Kurdieh, Mohamed S. Hasim, Shelby Kaczmarek, Zaid Taha, Glib Maznyi, Scott McComb, Seung-Hwan Lee, Jean-Simon Diallo and Michele Ardolino
Cancers 2022, 14(12), 2832; https://doi.org/10.3390/cancers14122832 - 08 Jun 2022
Viewed by 2250
Abstract
Due to their crucial role in tumor immunity, NK cells have quickly became a prime target for immunotherapies, with the adoptive transfer of NK cells and the use of NK cell engagers quickly moving to the clinical stage. On the other hand, only [...] Read more.
Due to their crucial role in tumor immunity, NK cells have quickly became a prime target for immunotherapies, with the adoptive transfer of NK cells and the use of NK cell engagers quickly moving to the clinical stage. On the other hand, only a few studies have focused on small molecule drugs capable of unleashing NK cells against cancer. In this context, repurposing small molecules is an attractive strategy to identify new immunotherapies from already approved drugs. Here, we developed a new platform to screen small molecule compounds based on a high-throughput luciferase-release cytotoxicity assay. We tested 1200 FDA approved drugs from the Prestwick Chemical Library, to identify compounds that increase NK cells’ cytotoxic potential. We found that the antibiotic colistin sulfate increased the cytotoxicity of human NK cells towards cancer cells. The effect of colistin was short lived and was not observed when NK cells were pretreated with the drug, showing how NK cell activity was potentiated only when the compound was present at the time of recognition of cancer cells. Further studies are needed to uncover the mechanism of action and the pre-clinical efficacy of colistin sulfate in mouse cancer models. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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15 pages, 2780 KiB  
Article
TIMP1 and TIMP2 Downregulate TGFβ Induced Decidual-like Phenotype in Natural Killer Cells
by Adriana Albini, Matteo Gallazzi, Maria Teresa Palano, Valentina Carlini, Riccardo Ricotta, Antonino Bruno, William G. Stetler-Stevenson and Douglas M. Noonan
Cancers 2021, 13(19), 4955; https://doi.org/10.3390/cancers13194955 - 01 Oct 2021
Cited by 15 | Viewed by 2776
Abstract
Natural Killer (NK) cells have been found to be anergic, exhausted and pro-angiogenic in cancers. NK cell from healthy donors, exposed to TGFβ, acquire the CD56brightCD9+CD49a+ decidual-like-phenotype, together with decreased levels of NKG2D activation marker, increased levels of [...] Read more.
Natural Killer (NK) cells have been found to be anergic, exhausted and pro-angiogenic in cancers. NK cell from healthy donors, exposed to TGFβ, acquire the CD56brightCD9+CD49a+ decidual-like-phenotype, together with decreased levels of NKG2D activation marker, increased levels of TIM-3 exhaustion marker, similar to cancer-associated NK cells. Tissue inhibitors of metalloproteases (TIMPs) exert dual roles in cancer. The role of TIMPs in modulating immune cells is a very novel concept, and the present is the first report studying their ability to contrast TGFβ action on NK cells. Here, we investigated the effects of TIMP1 and TIMP2 recombinant proteins in hindering decidual-like markers in NK cells, generated by polarizing cytolytic NK cells with TGFβ. The effects of TIMP1 or TIMP2 on NK cell surface antigens were determined by multicolor flow cytometry. We found that TIMP1 and TIMP2 were effective in interfering with TGFβ induced NK cell polarization towards a decidual-like-phenotype. TIMP1 and TIMP2 counteracted the effect of TGFβ in increasing the percentage of CD56bright, CD16−, CD9+ and CD49a+, and restoring normal levels for TIMP 1 and 2 also inhibited decrease levels of the activation marker NKG2D induced by TGFβ and decreased the TGFβ upregulated exhaustion marker TIM-3. NK cell degranulation capabilities against K562 cells were also decreased by TGFβ and not by TIMP1 or TIMP2. TIMP1 treatment could partially restore degranulation marker CD107a expression. Treatment with recombinant TIMP-1 or TIMP-2 showed a trend, although not statistically significant, to decrease CD49a+ and TIM-3+ expression and increase NKG2D in peripheral blood NK cells exposed to conditioned media from colon cancer cell lines. Our results suggest a potential role of TIMPs in controlling the tumor-associated cytokine TGFβ-induced NK cell polarization. Given the heterogeneity of released factors within the TME, it is clear that TGFβ stimulation represents a model to prove TIMP’s new properties, but it cannot be envisaged as a soloist NK cell polarizing agent. Therefore, further studies from the scientific community will help defining TIMPs immunomodulatory activities of NK cells in cancer, and their possible future diagnostic–therapeutic roles. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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22 pages, 2588 KiB  
Article
Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome
by Elisa Brandetti, Chiara Focaccetti, Annalisa Pezzolo, Marzia Ognibene, Valentina Folgiero, Nicola Cotugno, Monica Benvenuto, Paolo Palma, Vittorio Manzari, Paolo Rossi, Doriana Fruci, Roberto Bei and Loredana Cifaldi
Cancers 2021, 13(17), 4368; https://doi.org/10.3390/cancers13174368 - 29 Aug 2021
Cited by 6 | Viewed by 2638
Abstract
High-risk neuroblastoma (NB) is a rare childhood cancer whose aggressiveness is due to a variety of chromosomal genetic aberrations, including those conferring immune evasion. Indeed, NB cells adopt several molecular strategies to evade recognition by the immune system, including the downregulation of ligands [...] Read more.
High-risk neuroblastoma (NB) is a rare childhood cancer whose aggressiveness is due to a variety of chromosomal genetic aberrations, including those conferring immune evasion. Indeed, NB cells adopt several molecular strategies to evade recognition by the immune system, including the downregulation of ligands for NK-cell-activating receptors. To date, while molecular strategies aimed at enhancing the expression of ligands for NKG2D- and DNAM-1-activating receptors have been explored, no evidence has been reported on the immunomodulatory mechanisms acting on the expression of death receptors such as Fas in NB cells. Here, we demonstrated that transient overexpression of the NF-kB p65 subunit upregulates the surface expression of Fas and PVR, the ligand of DNAM-1, thus making NB cell lines significantly more susceptible to NK-cell-mediated apoptosis, recognition, and killing. In contrast, IFNγ and TNFα treatment, although it induced the upregulation of FAS in NB cells and consequently enhanced NK-cell-mediated apoptosis, triggered immune evasion processes, including the strong upregulation of MHC class I and IDO1, both of which are involved in mechanisms leading to the impairment of a proper NK-cell-mediated killing of NB. In addition, high-resolution array CGH analysis performed in our cohort of NB patients revealed that the loss of FAS and/or PVR genes correlated with low survival independently of the disease stage. Our data identify the status of the FAS and PVR genes as prognostic biomarkers of NB that may predict the efficacy of NK-cell-based immunotherapy of NB. Overall, restoration of surface expression of Fas and PVR, through transient upregulation of NF-kB, may be a clue to a novel NK-cell-based immunotherapy of NB. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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16 pages, 2813 KiB  
Article
A HER2 Tri-Specific NK Cell Engager Mediates Efficient Targeting of Human Ovarian Cancer
by Daniel A. Vallera, Felix Oh, Behiye Kodal, Peter Hinderlie, Melissa A. Geller, Jeffrey S. Miller and Martin Felices
Cancers 2021, 13(16), 3994; https://doi.org/10.3390/cancers13163994 - 08 Aug 2021
Cited by 24 | Viewed by 4926
Abstract
Clinical studies validated antibodies directed against HER2, trastuzumab, and pertuzumab, as useful methodology to target breast cancer cases where HER2 is expressed. The hope was that HER2 targeting using these antibodies in ovarian cancer patients would prove useful as well, but clinical studies [...] Read more.
Clinical studies validated antibodies directed against HER2, trastuzumab, and pertuzumab, as useful methodology to target breast cancer cases where HER2 is expressed. The hope was that HER2 targeting using these antibodies in ovarian cancer patients would prove useful as well, but clinical studies have shown lackluster results in this setting, indicating a need for a more comprehensive approach. Immunotherapy approaches stimulating the innate immune system show great promise, although enhancing natural killer (NK) function is not an established mainstream immunotherapy. This study focused on a new nanobody platform technology in which the bispecific antibody was altered to incorporate a cytokine. Herein we describe bioengineered CAM1615HER2 consisting of a camelid VHH antibody fragment recognizing CD16 and a single chain variable fragment (scFv) recognizing HER2 cross-linked by the human interleukin-15 (IL-15) cytokine. This tri-specific killer engager (TriKETM) showed in vitro prowess in its ability to kill ovarian cancer human cell lines. In addition, we demonstrated its efficacy in inducing potent anti-cancer effects in an in vivo xenograft model of human ovarian cancer engrafting both cancer cells and human NK cells. While previous approaches with trastuzumab and pertuzumab faltered in ovarian cancer, the hope is incorporating targeting and cytokine priming within the same molecule will enhance efficacy in this setting. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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10 pages, 944 KiB  
Article
Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients
by Takeji Umemura, Satoru Joshita, Hiromi Saito, Shun-ichi Wakabayashi, Hiroyuki Kobayashi, Yuki Yamashita, Ayumi Sugiura, Tomoo Yamazaki and Masao Ota
Cancers 2021, 13(13), 3267; https://doi.org/10.3390/cancers13133267 - 29 Jun 2021
Cited by 6 | Viewed by 1734
Abstract
Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C [...] Read more.
Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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18 pages, 2928 KiB  
Article
Phase I Trial of Prophylactic Donor-Derived IL-2-Activated NK Cell Infusion after Allogeneic Hematopoietic Stem Cell Transplantation from a Matched Sibling Donor
by Raynier Devillier, Boris Calmels, Sophie Guia, Mohammed Taha, Cyril Fauriat, Bechara Mfarrej, Geoffroy Venton, Eric Vivier, Daniel Olive, Christian Chabannon, Didier Blaise and Sophie Ugolini
Cancers 2021, 13(11), 2673; https://doi.org/10.3390/cancers13112673 - 28 May 2021
Cited by 12 | Viewed by 2749
Abstract
Background: NK cell-based immunotherapy to prevent relapse after allogeneic transplantation is an appealing strategy because NK cells can provide strong antitumor effect without inducing graft-versus-host disease (GVHD). Thus, we designed a phase-I clinical trial evaluating the safety of a prophylactic donor-derived ex [...] Read more.
Background: NK cell-based immunotherapy to prevent relapse after allogeneic transplantation is an appealing strategy because NK cells can provide strong antitumor effect without inducing graft-versus-host disease (GVHD). Thus, we designed a phase-I clinical trial evaluating the safety of a prophylactic donor-derived ex vivo IL-2 activated NK cell (IL-2 NK) infusion after allo-HSCT for patients with hematologic malignancies. Methods: Donor NK cells were purified and cultured ex vivo with IL-2 before infusion, at three dose levels. To identify the maximum tolerated dose was the main objective. In addition, we performed phenotypical and functional characterization of the NK cell therapy product, and longitudinal immune monitoring of NK cell phenotype in patients. Results: Compared to unstimulated NK cells, IL-2 NK cells expressed higher levels of activating receptors and exhibited increased degranulation and cytokine production in vitro. We treated 16 patients without observing any dose-limiting toxicity. At the last follow up, 11 out of 16 treated patients were alive in complete remission of hematologic malignancies without GVHD features and immunosuppressive treatment. Conclusions: Prophylactic donor-derived IL-2 NK cells after allo-HSCT is safe with low incidence of GVHD. Promising survivals and IL-2 NK cell activated phenotype may support a potential clinical efficacy of this strategy. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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19 pages, 6738 KiB  
Article
Defucosylation of Tumor-Specific Humanized Anti-MUC1 Monoclonal Antibody Enhances NK Cell-Mediated Anti-Tumor Cell Cytotoxicity
by Ying Gong, Roel G. J. Klein Wolterink, Valeriia Gulaia, Silvie Cloosen, Femke A. I. Ehlers, Lotte Wieten, Yvo F. Graus, Gerard M. J. Bos and Wilfred T. V. Germeraad
Cancers 2021, 13(11), 2579; https://doi.org/10.3390/cancers13112579 - 25 May 2021
Cited by 12 | Viewed by 3283
Abstract
Antibodies are commonly used in cancer immunotherapy because of their high specificity for tumor-associated antigens. The binding of antibodies can have direct effects on tumor cells but also engages natural killer (NK) cells via their Fc receptor. Mucin 1 (MUC1) is a highly [...] Read more.
Antibodies are commonly used in cancer immunotherapy because of their high specificity for tumor-associated antigens. The binding of antibodies can have direct effects on tumor cells but also engages natural killer (NK) cells via their Fc receptor. Mucin 1 (MUC1) is a highly glycosylated protein expressed in normal epithelial cells, while the under-glycosylated MUC1 epitope (MUC1-Tn/STn) is only expressed on malignant cells, making it an interesting diagnostic and therapeutic target. Several anti-MUC1 antibodies have been tested for therapeutic applications in solid tumors thus far without clinical success. Herein, we describe the generation of fully humanized antibodies based on the murine 5E5 antibody, targeting the tumor-specific MUC1-Tn/STn epitope. We confirmed that these antibodies specifically recognize tumor-associated MUC1 epitopes and can activate human NK cells in vitro. Defucosylation of these newly developed anti-MUC1 antibodies further enhanced antigen-dependent cellular cytotoxicity (ADCC) mediated by NK cells. We show that endocytosis inhibitors augment the availability of MUC1-Tn/STn epitopes on tumor cells but do not further enhance ADCC in NK cells. Collectively, this study describes novel fully humanized anti-MUC1 antibodies that, especially after defucosylation, are promising therapeutic candidates for cellular immunotherapy. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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19 pages, 3186 KiB  
Article
Expression of NK Cell Receptor Ligands on Leukemic Cells Is Associated with the Outcome of Childhood Acute Leukemia
by María Victoria Martínez-Sánchez, José Luis Fuster, José Antonio Campillo, Ana María Galera, Mar Bermúdez-Cortés, María Esther Llinares, Eduardo Ramos-Elbal, Juan Francisco Pascual-Gázquez, Ana María Fita, Helios Martínez-Banaclocha, José Antonio Galián, Lourdes Gimeno, Manuel Muro and Alfredo Minguela
Cancers 2021, 13(10), 2294; https://doi.org/10.3390/cancers13102294 - 11 May 2021
Cited by 8 | Viewed by 2458
Abstract
Acute leukemia is the most common malignancy in children. Most patients are cured, but refractory/relapsed AML and ALL are the first cause of death from malignancy in children. Maintenance chemotherapy in ALL has improved survival by inducing leukemic cell apoptosis, but immune surveillance [...] Read more.
Acute leukemia is the most common malignancy in children. Most patients are cured, but refractory/relapsed AML and ALL are the first cause of death from malignancy in children. Maintenance chemotherapy in ALL has improved survival by inducing leukemic cell apoptosis, but immune surveillance effectors such as NK cells might also contribute. The outcome of B-ALL (n = 70), T-ALL (n = 16), and AML (n = 16) pediatric patients was evaluated according to leukemic cell expression of ligands for activating and inhibiting receptors that regulate NK cell functioning. Increased expression of ULBP-1, a ligand for NKG2D, but not that of CD112 or CD155, ligands for DNAM-1, was associated with poorer 5-year event-free survival (5y-EFS, 77.6% vs. 94.9%, p < 0.03). Reduced expression of HLA-C on leukemic cells in patients with the KIR2DL1/HLA-C*04 interaction was associated with a higher rate of relapse (17.6% vs. 4.4%, p = 0.035) and lower 5y-EFS (70.6% vs. 92.6%, p < 0.002). KIR2DL1/HLA-C*04 interaction was an independent predictive factor of events (HR = 4.795, p < 0.005) or death (HR = 6.731, p < 0.005) and might provide additional information to the current risk stratification. Children who carry the KIR2DL1/HLA-C*04 interaction were refractory to current chemotherapy treatments, including allogeneic stem cell transplantation; therefore, they should be considered as candidates for alternative biological therapies that might offer better results. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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23 pages, 3350 KiB  
Article
Hypoxia-Driven HIF-1α Activation Reprograms Pre-Activated NK Cells towards Highly Potent Effector Phenotypes via ERK/STAT3 Pathways
by Seon Ah Lim, Yunwon Moon, Min Hwa Shin, Tae-Jin Kim, Sehyun Chae, Cassian Yee, Daehee Hwang, Hyunsung Park and Kyung-Mi Lee
Cancers 2021, 13(8), 1904; https://doi.org/10.3390/cancers13081904 - 15 Apr 2021
Cited by 18 | Viewed by 4213
Abstract
NK cells are the predominant innate lymphocyte subsets specialized to kill malignant tumor cells. In patients with advanced cancer, hypoxic stress shapes NK cells toward tumor-resistant and immunosuppressive phenotypes, hence a strategy to restore NK function is critical for successful tumor immunotherapy. Here, [...] Read more.
NK cells are the predominant innate lymphocyte subsets specialized to kill malignant tumor cells. In patients with advanced cancer, hypoxic stress shapes NK cells toward tumor-resistant and immunosuppressive phenotypes, hence a strategy to restore NK function is critical for successful tumor immunotherapy. Here, we present evidence that pre-activation and subsequent HIF-1α-dependent metabolic shift of NK cells from oxidative phosphorylation into glycolysis are keys to overcome hypoxia-mediated impairment in NK cell survival, proliferation, and tumor cytotoxicity. Specifically, exposing NK cells to 7–9 days of normoxic culture followed by a pO2 of 1.5% hypoxia led to a highly potent effector phenotype via HIF-1α stabilization and upregulation of its target genes, BNIP3, PDK1, VEGF, PKM2, and LDHA. RNA sequencing and network analyses revealed that concomitant reduction of p21/p53 apoptotic pathways along with upregulation of cell cycle-promoting genes, CCNE1, CDC6, CDC20, and downregulation of cell cycle-arrest genes, CDKN1A, GADD45A, and MDM2 were accountable for superior expansion of NK cells via ERK/STAT3 activation. Furthermore, HIF-1α-dependent upregulation of the NKp44 receptor in hypoxia-exposed NK cells resulted in increased killing against K562, CEM, and A375 tumor targets both in-vitro and in-vivo tumor clearance assays. Therefore, hypoxic exposure on pre-activated proliferating NK cells triggered HIF-1α-dependent pathways to initiate coordinated regulation of cell cycle, apoptosis, and cytotoxicity at the global gene transcription level. Our results uncover a previously unidentified role of HIF-1α-mediated metabolic reprogramming that can reverse impaired NK effector phenotypes to generate requisite numbers of functionally robust NK cells for adoptive cellular therapy for clinical evaluation. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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14 pages, 2090 KiB  
Article
Specific Patterns of Blood ILCs in Metastatic Melanoma Patients and Their Modulations in Response to Immunotherapy
by Louise Rethacker, Marie Roelens, Claudia Bejar, Eve Maubec, Hélène Moins-Teisserenc and Anne Caignard
Cancers 2021, 13(6), 1446; https://doi.org/10.3390/cancers13061446 - 22 Mar 2021
Cited by 12 | Viewed by 2815
Abstract
Immunotherapy targeting immune checkpoint receptors brought a breakthrough in the treatment of metastatic melanoma patients. However, a number of patients still resist these immunotherapies. Present on CD8+T cells, immune checkpoint receptors are expressed by innate lymphoid cells (ILCs), which may contribute [...] Read more.
Immunotherapy targeting immune checkpoint receptors brought a breakthrough in the treatment of metastatic melanoma patients. However, a number of patients still resist these immunotherapies. Present on CD8+T cells, immune checkpoint receptors are expressed by innate lymphoid cells (ILCs), which may contribute to the clinical response. ILCs are composed of natural killer (NK) cells, which are cytotoxic effectors involved in tumor immunosurveillance. NK cell activation is regulated by a balance between activating receptors that detect stress molecules on tumor cells and HLA-I-specific inhibitory receptors. Helper ILCs (h-ILCs) are newly characterized ILCs that secrete cytokines and regulate the immune homeostasis of tissue. We investigated the modulation of blood ILCs in melanoma patients treated with ipilimumab. Circulating ILCs from metastatic stage IV melanoma patients and healthy donors were studied for their complete phenotypic status. Patients were studied before and at 3, 6, and 12 weeks of ipilimumab treatment. A comparison of blood ILC populations from donors and melanoma patients before treatment showed changes in proportions of ILC subsets, and a significant inverse correlation of CD56dim NK cells and h-ILC subsets was identified in patients. During treatment with ipilimumab, percentages of all ILC subsets were reduced. Ipilimumab also impacted the expression of the CD96/TIGIT/DNAM-1 pathway in all ILCs and increased CD161 and CTLA-4 expression by h-ILCs. When considering the response to the treatment, patients without disease control were characterized by higher percentages of CD56bright NK cells and ILC1. Patients with disease control displayed larger populations of activated CD56dimCD16+ DNAM-1+ NK cells, while anergic CD56dimCD16−DNAM-1− NK cells were prominent in patients without disease control. These results provide original findings on the distribution of ILC subsets in advanced melanoma patients and their modulation through immunotherapy. The effects of ipilimumab on these ILC subsets may critically influence therapeutic outcomes. These data indicate the importance of considering these innate cell subsets in immunotherapeutic strategies for melanoma patients. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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15 pages, 8254 KiB  
Article
Adapter Chimeric Antigen Receptor (AdCAR)-Engineered NK-92 Cells for the Multiplex Targeting of Bone Metastases
by Stefan Grote, Frank Traub, Joerg Mittelstaet, Christian Seitz, Andrew Kaiser, Rupert Handgretinger and Sabine Schleicher
Cancers 2021, 13(5), 1124; https://doi.org/10.3390/cancers13051124 - 05 Mar 2021
Cited by 4 | Viewed by 2646
Abstract
Background: Since metastatic spreading of solid tumor cells often leads to a fatal outcome for most cancer patients, new approaches for patient-individualized, targeted immunotherapy are urgently needed. Methods: Here, we established cell lines from four bone metastases of different tumor entities. We assessed [...] Read more.
Background: Since metastatic spreading of solid tumor cells often leads to a fatal outcome for most cancer patients, new approaches for patient-individualized, targeted immunotherapy are urgently needed. Methods: Here, we established cell lines from four bone metastases of different tumor entities. We assessed AdCAR NK-92-mediated cytotoxicity in vitro in standard cytotoxicity assays as well as 3D spheroid models Results: AdCAR-engineered NK-92 cells successfully demonstrated distinct and specific cytotoxic potential targeting different tumor antigens expressed on cell lines established from bone metastases of mammary, renal cell and colorectal carcinoma as well as melanomas. In that process AdCAR NK-92 cells produced a multitude of NK effector molecules as well as pro inflammatory cytokines. Furthermore, AdCAR NK-92 showed increased cytotoxicity in 3D spheroid models which can recapitulate in vivo architecture, thereby bridging the gap between in vitro and in vivo models. Conclusions: AdCAR NK-92 cells may provide an interesting and promising “off-the-shelf” cellular product for the targeted therapy of cancers metastasizing to the bone, while utilization of clinically approved, therapeutic antibodies, as exchangeable adapter molecules can facilitate quick clinical translation. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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15 pages, 3059 KiB  
Article
An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma
by Stefania Mantovani, Stefania Varchetta, Dalila Mele, Matteo Donadon, Guido Torzilli, Cristiana Soldani, Barbara Franceschini, Camillo Porta, Silvia Chiellino, Paolo Pedrazzoli, Roberto Santambrogio, Matteo Barabino, Claudia Cigala, Gaetano Piccolo, Enrico Opocher, Marcello Maestri, Angelo Sangiovanni, Stefano Bernuzzi, Florence Lhospice, Manel Kraiem, Mario Umberto Mondelli and Barbara Olivieroadd Show full author list remove Hide full author list
Cancers 2020, 12(12), 3583; https://doi.org/10.3390/cancers12123583 - 30 Nov 2020
Cited by 16 | Viewed by 3351
Abstract
Natural killer (NK) cells play a pivotal role in cancer immune surveillance, and activating the receptor/ligand interaction may contribute to control the development and evolution of hepatocellular carcinoma (HCC). We investigated the role of the natural killer group 2 member D (NKG2D) activating [...] Read more.
Natural killer (NK) cells play a pivotal role in cancer immune surveillance, and activating the receptor/ligand interaction may contribute to control the development and evolution of hepatocellular carcinoma (HCC). We investigated the role of the natural killer group 2 member D (NKG2D) activating receptor and its ligand, the major histocompatibility complex class I chain-related protein A and B (MICA/B) in patients with cirrhosis and HCC subjected to surgical resection, patients with cirrhosis and no HCC, and healthy donors (HD). The NKG2D-mediated function was determined in peripheral blood (PB), in tumor-infiltrating lymphocytes (NK-TIL), and in matched surrounding liver tissue (NK-LIL). A group of patients treated with sorafenib because of clinically advanced HCC was also studied. A humanized anti-MICA/B monoclonal antibody (mAb) was used in in vitro experiments to examine NK cell-mediated antibody-dependent cellular cytotoxicity. Serum concentrations of soluble MICA/B were evaluated by ELISA. IL-15 stimulation increased NKG2D-dependent activity which, however, remained dysfunctional in PB NK cells from HCC patients, in line with the reduced NKG2D expression on NK cells. NK-TIL showed a lower degranulation ability than NK-LIL, which was restored by IL-15 stimulation. Moreover, in vitro IL-15 stimulation enhanced degranulation and interferon-γ production by PB NK from patients at month one of treatment with sorafenib. Anti-MICA/B mAb associated with IL-15 was able to induce PB NK cytotoxicity for primary HCC cells in HD and patients with HCC, who also showed NK-TIL degranulation for autologous primary HCC cells. Our findings highlight the key role of the NKG2D-MICA/B axis in the regulation of NK cell responses in HCC and provide evidence in support of a potentially important role of anti-MICA/B mAb and IL-15 stimulation in HCC immunotherapy. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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Review

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23 pages, 1910 KiB  
Review
NK Cells in Myeloproliferative Neoplasms (MPN)
by Erin Naismith, Janine Steichen, Sieghart Sopper and Dominik Wolf
Cancers 2021, 13(17), 4400; https://doi.org/10.3390/cancers13174400 - 31 Aug 2021
Viewed by 2969
Abstract
Myeloproliferative neoplasms (MPNs) comprise a heterogenous group of hematologic neoplasms which are divided into Philadelphia positive (Ph+), and Philadelphia negative (Ph−) or classical MPNs. A variety of immunological factors including inflammatory, as well as immunomodulatory processes, closely interact with the disease phenotypes in [...] Read more.
Myeloproliferative neoplasms (MPNs) comprise a heterogenous group of hematologic neoplasms which are divided into Philadelphia positive (Ph+), and Philadelphia negative (Ph−) or classical MPNs. A variety of immunological factors including inflammatory, as well as immunomodulatory processes, closely interact with the disease phenotypes in MPNs. NK cells are important innate immune effectors and substantially contribute to tumor control. Changes to the absolute and proportionate numbers of NK cell, as well as phenotypical and functional alterations are seen in MPNs. In addition to the disease itself, a variety of therapeutic options in MPNs may modify NK cell characteristics. Reports of suppressive effects of MPN treatment strategies on NK cell activity have led to intensive investigations into the respective compounds, to elucidate the possible negative effects of MPN therapy on control of the leukemic clones. We hereby review the available literature on NK cells in Ph+ and Ph− MPNs and summarize today’s knowledge on disease-related alterations in this cell compartment with particular focus on known therapy-associated changes. Furthermore, we critically evaluate conflicting data with possible implications for future projects. We also aim to highlight the relevance of full NK cell functionality for disease control in MPNs and the importance of considering specific changes related to therapy in order to avoid suppressive effects on immune surveillance. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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25 pages, 982 KiB  
Review
Inhibitory Receptors and Immune Checkpoints Regulating Natural Killer Cell Responses to Cancer
by Irina Buckle and Camille Guillerey
Cancers 2021, 13(17), 4263; https://doi.org/10.3390/cancers13174263 - 24 Aug 2021
Cited by 30 | Viewed by 8204
Abstract
The discovery of immune checkpoints provided a breakthrough for cancer therapy. Immune checkpoints are inhibitory receptors that are up-regulated on chronically stimulated lymphocytes and have been shown to hinder immune responses to cancer. Monoclonal antibodies against the checkpoint molecules PD-1 and CTLA-4 have [...] Read more.
The discovery of immune checkpoints provided a breakthrough for cancer therapy. Immune checkpoints are inhibitory receptors that are up-regulated on chronically stimulated lymphocytes and have been shown to hinder immune responses to cancer. Monoclonal antibodies against the checkpoint molecules PD-1 and CTLA-4 have shown early clinical success against melanoma and are now approved to treat various cancers. Since then, the list of potential candidates for immune checkpoint blockade has dramatically increased. The current paradigm stipulates that immune checkpoint blockade therapy unleashes pre-existing T cell responses. However, there is accumulating evidence that some of these immune checkpoint molecules are also expressed on Natural Killer (NK) cells. In this review, we summarize our latest knowledge about targetable NK cell inhibitory receptors. We discuss the HLA-binding receptors KIRS and NKG2A, receptors binding to nectin and nectin-like molecules including TIGIT, CD96, and CD112R, and immune checkpoints commonly associated with T cells such as PD-1, TIM-3, and LAG-3. We also discuss newly discovered pathways such as IL-1R8 and often overlooked receptors such as CD161 and Siglecs. We detail how these inhibitory receptors might regulate NK cell responses to cancer, and, where relevant, we discuss their implications for therapeutic intervention. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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19 pages, 1099 KiB  
Review
The Role of Natural Killer Cells in Soft Tissue Sarcoma: Prospects for Immunotherapy
by Tânia Fortes-Andrade, Jani Sofia Almeida, Luana Madalena Sousa, Manuel Santos-Rosa, Paulo Freitas-Tavares, José Manuel Casanova and Paulo Rodrigues-Santos
Cancers 2021, 13(15), 3865; https://doi.org/10.3390/cancers13153865 - 31 Jul 2021
Cited by 4 | Viewed by 2878
Abstract
Soft-tissue sarcomas (STS) represent about 80% of sarcomas, and are a heterogeneous group of rare and malignant tumors. STS arise from mesenchymal tissues and can grow into structures such as adipose tissue, muscles, nervous tissue and blood vessels. Morphological evaluation has been the [...] Read more.
Soft-tissue sarcomas (STS) represent about 80% of sarcomas, and are a heterogeneous group of rare and malignant tumors. STS arise from mesenchymal tissues and can grow into structures such as adipose tissue, muscles, nervous tissue and blood vessels. Morphological evaluation has been the standard model for the diagnosis of sarcomas, and even in samples with similar characteristics, they present a diversity in cytogenetic and genetic sequence alterations, which further increases the diversity of sarcomas. This variety is one of the main challenges for the classification and understanding of STS patterns, as well as for their respective treatments, which further decreases patient survival (<5 years). Despite some studies, little is known about the immunological profile of STS. As for the immunological profile of STS in relation to NK cells, there is also a shortage of studies. Observations made in solid tumors show that the infiltration of NK cells in tumors is associated with a good prognosis of the disease. Notwithstanding the scarcity of studies to characterize NK cells, their receptors, and ligands in STS, it is noteworthy that the progression of these malignancies is associated with altered NK phenotypes. Despite the scarcity of information on the function of NK cells, their phenotypes and their regulatory pathways in STS, the findings of this study support the additional need to explore NK cell-based immunotherapy in STS further. Some clinical trials, very tentatively, are already underway. STS clinical trials are still the basis for adoptive NK-cell and cytokine-based therapy. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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22 pages, 2362 KiB  
Review
Three-Dimensional Culture Models to Study Innate Anti-Tumor Immune Response: Advantages and Disadvantages
by Alessandro Poggi, Federico Villa, Jordi Leonardo Castrillo Fernadez, Delfina Costa, Maria Raffaella Zocchi and Roberto Benelli
Cancers 2021, 13(14), 3417; https://doi.org/10.3390/cancers13143417 - 08 Jul 2021
Cited by 15 | Viewed by 4447
Abstract
Several approaches have shown that the immune response against tumors strongly affects patients’ clinical outcome. Thus, the study of anti-tumor immunity is critical to understand and potentiate the mechanisms underlying the elimination of tumor cells. Natural killer (NK) cells are members of innate [...] Read more.
Several approaches have shown that the immune response against tumors strongly affects patients’ clinical outcome. Thus, the study of anti-tumor immunity is critical to understand and potentiate the mechanisms underlying the elimination of tumor cells. Natural killer (NK) cells are members of innate immunity and represent powerful anti-tumor effectors, able to eliminate tumor cells without a previous sensitization. Thus, the study of their involvement in anti-tumor responses is critical for clinical translation. This analysis has been performed in vitro, co-incubating NK with tumor cells and quantifying the cytotoxic activity of NK cells. In vivo confirmation has been applied to overcome the limits of in vitro testing, however, the innate immunity of mice and humans is different, leading to discrepancies. Different activating receptors on NK cells and counter-ligands on tumor cells are involved in the antitumor response, and innate immunity is strictly dependent on the specific microenvironment where it takes place. Thus, three-dimensional (3D) culture systems, where NK and tumor cells can interact in a tissue-like architecture, have been created. For example, tumor cell spheroids and primary organoids derived from several tumor types, have been used so far to analyze innate immune response, replacing animal models. Herein, we briefly introduce NK cells and analyze and discuss in detail the properties of 3D tumor culture systems and their use for the study of tumor cell interactions with NK cells. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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18 pages, 2299 KiB  
Review
Immune Circuits to Shape Natural Killer Cells in Cancer
by Irene Mattiola
Cancers 2021, 13(13), 3225; https://doi.org/10.3390/cancers13133225 - 28 Jun 2021
Cited by 15 | Viewed by 6498
Abstract
Natural killer (NK) cells are innate lymphoid cells playing an important role in anti-cancer immunity. NK cells are efficient in controlling the spreading of metastasis but are not very powerful in fighting against primary tumors. The NK cell capability to infiltrate and persist [...] Read more.
Natural killer (NK) cells are innate lymphoid cells playing an important role in anti-cancer immunity. NK cells are efficient in controlling the spreading of metastasis but are not very powerful in fighting against primary tumors. The NK cell capability to infiltrate and persist in the tumor microenvironment and to exert their antitumoral functions is often limited by tumor escape mechanisms. These tumor-mediated strategies not only induce NK cell tolerance but also interfere with the NK cell-dependent immune networking. This review will provide an overview of the tumor escape mechanisms impacting NK cells, identify the immune circuits regulating the NK cell-dependent antitumor immunity and revise the emerging therapeutic approaches to unleash NK cells in cancer. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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15 pages, 838 KiB  
Review
Natural Killer Cells in Post-Transplant Lymphoproliferative Disorders
by Cecilia Nakid-Cordero, Marine Baron, Amélie Guihot and Vincent Vieillard
Cancers 2021, 13(8), 1836; https://doi.org/10.3390/cancers13081836 - 12 Apr 2021
Cited by 4 | Viewed by 2332
Abstract
Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications arising after solid organ or hematopoietic stem cell transplantations. Although the majority of these lymphoproliferations are of B cell origin, and are frequently associated with primary Epstein–Barr virus (EBV) infection or reactivation in the post-transplant period, [...] Read more.
Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications arising after solid organ or hematopoietic stem cell transplantations. Although the majority of these lymphoproliferations are of B cell origin, and are frequently associated with primary Epstein–Barr virus (EBV) infection or reactivation in the post-transplant period, rare cases of T cell and natural killer (NK) cell-originated PTLDs have also been described. A general assumption is that PTLDs result from the impairment of anti-viral and anti-tumoral immunosurveillance due to the long-term use of immunosuppressants in transplant recipients. T cell impairment is known to play a critical role in the immune-pathogenesis of post-transplant EBV-linked complications, while the role of NK cells has been less investigated, and is probably different between EBV-positive and EBV-negative PTLDs. As a part of the innate immune response, NK cells are critical for protecting hosts during the early response to virus-induced tumors. The complexity of their function is modulated by a myriad of activating and inhibitory receptors expressed on cell surfaces. This review outlines our current understanding of NK cells in the pathogenesis of PTLD, and discusses their potential implications for current PTLD therapies and novel NK cell-based therapies for the containment of these disorders. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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20 pages, 9294 KiB  
Review
Human NK Cells in Autologous Hematopoietic Stem Cell Transplantation for Cancer Treatment
by Ane Orrantia, Iñigo Terrén, Gabirel Astarloa-Pando, Olatz Zenarruzabeitia and Francisco Borrego
Cancers 2021, 13(7), 1589; https://doi.org/10.3390/cancers13071589 - 30 Mar 2021
Cited by 7 | Viewed by 3925
Abstract
Natural killer (NK) cells are phenotypically and functionally diverse lymphocytes with the ability to recognize and kill malignant cells without prior sensitization, and therefore, they have a relevant role in tumor immunosurveillance. NK cells constitute the main lymphocyte subset in peripheral blood in [...] Read more.
Natural killer (NK) cells are phenotypically and functionally diverse lymphocytes with the ability to recognize and kill malignant cells without prior sensitization, and therefore, they have a relevant role in tumor immunosurveillance. NK cells constitute the main lymphocyte subset in peripheral blood in the first week after hematopoietic stem cell transplantation (HSCT). Although the role that NK cells play in allogenic HSCT settings has been documented for years, their significance and beneficial effects associated with the outcome after autologous HSCT are less recognized. In this review, we have summarized fundamental aspects of NK cell biology, such as, NK cell subset diversity, their effector functions, and differentiation. Moreover, we have reviewed the factors that affect autologous HSCT outcome, with particular attention to the role played by NK cells and their receptor repertoire in this regard. Full article
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
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