Article
Immunology
Cristina Capuano, Davide De Federicis, Daniel Ciuti, Ombretta Turriziani, Antonio Angeloni, Emanuela Anastasi, Giuseppe Giannini, Francesca Belardinilli, Rosa Molfetta, Domenico Alvaro, Gabriella Palmieri, Ricciarda Galandrini
Summary: This study demonstrates a durable downmodulation of CD16 levels and antibody-dependent NK cell functions after SARS-CoV-2 heterologous vaccination, and highlights the impact of genetic and environmental host-related factors in modulating NK cell susceptibility to post-vaccinal Fc-dependent functional impairment.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Genetics & Heredity
Hannes Vietzen, Vera Danklmaier, Alexander Zoufaly, Elisabeth Puchhammer-Stockl
Summary: This study investigates the role of genetic variants in activating natural killer (NK) cell receptors in contributing to the severity of COVID-19. The study shows that the high-affinity variant of the Fc gamma RIIIa receptor is over-represented in hospitalized and deceased patients with COVID-19, while the low-affinity variant is more common in patients with mild COVID-19. Additionally, functional assays reveal that hospitalized patients with COVID-19 exhibit significantly higher proinflammatory ADCC responses, particularly in NK cells expressing the high-affinity variant of the Fc gamma RIIIa receptor.
GENETICS IN MEDICINE
(2022)
Review
Oncology
Kate J. Dixon, Jianming Wu, Bruce Walcheck
Summary: Human natural killer (NK) cells target tumor antigens through interaction with IgG Fc receptors, leading to antibody-dependent cell-mediated cytotoxicity (ADCC) against cancer cells. Engineering monoclonal antibodies and Fc receptors can enhance NK cell-mediated ADCC for cancer treatment. Targeting tumor antigens by modifying the Fc portion of antibodies or the FcR on NK cells is a key focus of research in improving mAb therapy efficacy.
Article
Cell Biology
Oscar A. Aguilar, Maria D. R. Gonzalez-Hinojosa, Janice S. Arakawa-Hoyt, Alberto J. Millan, Dagmar Gotthardt, Tsukasa Nabekura, Lewis L. Lanier
Summary: In this study, the expression and biological consequences of activating mouse NK cells through their Fc gamma receptors were characterized. It was found that most NK cells express the activating CD16 receptor, and a subset of NK cells also expresses the inhibitory CD32b receptor. These Fc gamma receptors are functional and can modulate antibody-mediated immune responses.
JOURNAL OF LEUKOCYTE BIOLOGY
(2023)
Article
Immunology
H. A. Daniel Lagasse, Louis B. Hopkins, Wojciech Jankowski, Marc G. Jacquemin, Zuben E. Sauna, Basil Golding
Summary: The most challenging complication associated with Factor VIII (FVIII) replacement therapy is the development of neutralizing anti-drug antibodies, which occur in a significant percentage of severe hemophilia A patients. Strategies to prevent or tolerize individuals with these antibodies are crucial, with immune tolerance induction (ITI) therapy being the only clinically proven method. Research suggests that Factor VIII Fc-fusion (rFVIIIFc) may be more effective in managing patients with anti-FVIII inhibitors compared to other FVIII products.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Multidisciplinary Sciences
Derek Lee, Zachary Spencer Dunn, Wenbin Guo, Carl J. Rosenthal, Natalie E. Penn, Yanqi Yu, Kuangyi Zhou, Zhe Li, Feiyang Ma, Miao Li, Tsun-Ching Song, Xinjian Cen, Yan-Ruide Li, Jin J. Zhou, Matteo Pellegrini, Pin Wang, Lili Yang
Summary: Vγ9Vδ2 (Vδ2) T cells are proposed as cell carriers for off-the-shelf CAR therapies. CD16 is identified as a biomarker for selecting Vδ2 T cells with high cytotoxicity, and engineered CD16high Vδ2 T cells demonstrate anti-tumor activity in ovarian cancer preclinical models.
NATURE COMMUNICATIONS
(2023)
Article
Immunology
Sebastian Lutz, Katja Klausz, Anca-Maria Albici, Lea Ebinger, Lea Sellmer, Hannah Teipel, Andre Frenzel, Anna Langner, Dorothee Winterberg, Steffen Krohn, Michael Hust, Thomas Schirrmann, Stefan Duebel, Regina Scherliess, Andreas Humpe, Martin Gramatzki, Christian Kellner, Matthias Peipp
Summary: This study successfully activated natural killer cells and induced lysis of lymphoma cells by preparing novel bispecific antibodies. The study also found that co-administration with specific monoclonal antibodies or bispecific T cell engagers enhanced antibody-dependent cell-mediated cytotoxicity and T cell activation. Furthermore, the study proposed a combinatorial approach targeting multiple tumor antigens, which has the potential to optimize antibody cancer therapies.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Virology
Hannes Vietzen, Philippe L. Furlano, Marianna Traugott, David Totschnig, Wolfgang Hoepler, Robert Strassl, Alexander Zoufaly, Elisabeth Puchhammer-Stoeckl
Summary: The severity of COVID-19 is influenced by genetic factors, such as variations in the HLA-E, Fc gamma RIIIa, and NKG2C receptors affecting natural killer (NK) cell responses. A genetic polymorphism known as rs9916629-C/T was found to impact the development of pro-inflammatory NK cells and was associated with fatal COVID-19. In this study, the rs9916629-C/T variants were investigated for their association with fatal COVID-19 in hospitalized patients. The presence of the rs9916629-C allele was identified as a risk factor for severe and fatal COVID-19, independent of age or comorbidities. Fatal COVID-19 was more common in younger patients with the Fc gamma RIIIa-158-V/V variant and in older patients with the KLRC2(del) variant. Therefore, the identification of rs9916629-C/T variants may serve as a prognostic marker for fatal COVID-19 in hospitalized patients.
JOURNAL OF MEDICAL VIROLOGY
(2023)
Article
Medicine, Research & Experimental
Da Chen, Yingjie Zhao, Mingyu Li, Hang Shang, Na Li, Fan Li, Wei Wang, Yuan Wang, Ruina Jin, Shiyu Liu, Xun Li, Shan Gao, Yujie Tian, Ruonan Li, Huanhuan Li, Yongyan Zhang, Mingjuan Du, Youjia Cao, Yan Zhang, Xin Li, Yi Huang, Liaoyuan A. Hu, Fubin Li, Hongkai Zhang
Summary: Fc engineering has become a focus in antibody drug development. A mammalian cell display-based platform was developed to screen millions of Fc variants for optimized binding to Fc gamma RIIIa or Fc gamma RIIb. Novel Fc variants with enhanced binding and improved effector function were successfully identified.
Article
Immunology
William D. D. Tolbert, Neelakshi Gohain, Paul G. G. Kremer, Andrew P. P. Hederman, Dung N. N. Nguyen, Verna Van, Rebekah Sherburn, George K. K. Lewis, Andres Finzi, Justin Pollara, Margaret E. E. Ackerman, Adam W. W. Barb, Marzena Pazgier
Summary: Fc mediated effector functions of antibodies are crucial in immunotherapies and vaccine efficacy. The Ile/Val(158) polymorphism in Mm Fc gamma RIII and glycan composition variations affect the affinity of allelic variants, providing important insights for nonhuman primate studies and human effector cell studies.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Oncology
Kawaljit Kaur, Tahmineh Safaie, Meng-Wei Ko, Yuhao Wang, Anahid Jewett
Summary: Natural killer cells can eliminate tumors through direct cytotoxicity and antibody dependent cellular cytotoxicity. The use of antibodies targeting specific surface receptors can enhance antibody dependent cellular cytotoxicity. CD16 receptors may mediate both direct cytotoxicity and antibody dependent cellular cytotoxicity, leading to competitive usage depending on differentiation status of tumor cells and activation stage of NK cells.
Article
Oncology
Fei Gao, Mauricio Campos Mora, Michael Constantinides, Lois Coenon, Caroline Multrier, Loic Vaillant, Tianxiang Zhang, Martin Villalba
Summary: This study found significant phenotypical and functional differences between g-NK cells in umbilical cord blood and peripheral blood. Unlike g-NK cells in peripheral blood, g-NK cells in umbilical cord blood do not show heightened cytokine production upon CD16 engagement. However, they exhibit elevated levels of IFN-gamma production after in vitro activation, particularly when co-cultured with human cytomegalovirus and plasma from g-NK positive adults.
Article
Multidisciplinary Sciences
Denise H. J. Habets, Salwan Al-Nasiry, Sietse Q. Nagelkerke, Christina E. M. Voorter, Marc E. A. Spaanderman, Taco W. Kuijpers, Lotte Wieten
Summary: This study found that the p.Val176Phe polymorphism in the FCGR3A gene is associated with recurrent pregnancy loss. Patients with at least one p.176Val variant showed increased expression of CD16a receptor and anti-HLA antibodies. However, there was no association between FCGR3A-p.176 polymorphism and the presence of class I and class II anti-HLA antibodies.
SCIENTIFIC REPORTS
(2023)
Article
Biology
Weiru Liu
Summary: Natural killer (NK) cells play an important role in monitoring the health of neighboring cells through various receptors. CD16, a receptor for IgG, mediates antibody-dependent cellular cytotoxicity (ADCC) and connects innate and adaptive immunities. There is interest in genetically engineering NK cells to enhance ADCC for improved clinical outcomes. This study presents a new protocol that uses immobilized anti-CD16 antibodies to evaluate NK cell ADCC, reducing experimental time.
Review
Immunology
Sheena Pinto, Jens Pahl, Arndt Schottelius, Paul J. Carter, Joachim Koch
Summary: Bi-, tri- and multispecific antibodies have revolutionized targeted cancer immunotherapies, allowing immune effector cells to selectively eliminate malignant cells. However, there are still major challenges to overcome, such as enhancing efficacy in solid tumors and minimizing toxicities and immunogenicity.
TRENDS IN IMMUNOLOGY
(2022)
Article
Oncology
Chiara Nicolazzo, Francesca Belardinilli, Annarita Vestri, Valentina Magri, Gianluigi De Renzi, Michela De Meo, Salvatore Caponnetto, Federica Di Nicolantonio, Enrico Cortesi, Giuseppe Giannini, Paola Gazzaniga
Summary: Liquid biopsies have revealed that the conversion from RAS mutant to RAS wild-type status is a common occurrence in RAS mutant colorectal cancer, indicating a negative selection of RAS mutant clones during the course of the disease. This study aimed to investigate whether the negative selection of RAS mutation in plasma is dependent on drug treatment. The results showed that the use of bevacizumab was significantly associated with the conversion to RAS wild-type status. Patients who converted to RAS wild-type status after bevacizumab treatment had a longer progression-free survival compared to those who remained RAS mutant, suggesting that they could be candidates for second-line treatment with anti-EGFR drugs.
Article
Immunology
Nadia D. Milito, Alessandra Zingoni, Helena Stabile, Alessandra Soriani, Cristina Capuano, Marco Cippitelli, Angela Gismondi, Angela Santoni, Rossella Paolini, Rosa Molfetta
Summary: The activation of natural killer (NK) cells is influenced by activating and inhibitory receptors which aid in identifying diseased cells. Among these receptors, NKG2D and DNAM-1 are crucial for the immune response against cancer as they bind to ligands expressed on transformed cells. However, during tumor progression, these receptors are often downregulated and lose their functionality. NKG2D internalization has been associated with dysfunctional phenotype characterized by tolerance to other activating receptors. Nevertheless, the consequences of NKG2D engagement are still incompletely understood. In this study, we demonstrate that NKG2D engagement impairs DNAM-1-mediated killing on human NK cells through two converging mechanisms: upregulation of the inhibitory receptor TIGIT, which suppresses DNAM-1-mediated cytotoxic function, and direct inhibition of DNAM-1 signaling. These findings reveal a novel interplay between NKG2D and DNAM-1/TIGIT receptors that may enable neoplastic cells to evade clearance by NK cells.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2023)
Review
Cell Biology
Rosa Molfetta, Rossella Paolini
Summary: Mast cells are tissue-resident sentinels involved in various physiological and pathological processes. They are frequently observed in tumor microenvironments, but their role in tumor initiation and growth is still controversial.
Article
Rheumatology
Lucia Novelli, Cristiana Barbati, Cristina Capuano, Serena Recalchi, Fulvia Ceccarelli, Marta Vomero, Cristiano Alessandri, Stefania Morrone, Fabrizio Conti
Summary: This study investigated the expression of KLRG1 in SLE patients compared to healthy controls on both NK and T cells, as well as its possible involvement in SLE pathogenesis. The results showed that KLRG1 expression was significantly reduced on immune cell populations in SLE patients, especially on total NK cells. In addition, KLRG1 expression on NK cells was inversely correlated with disease activity and associated with treatment with HCQ. In vitro treatment with HCQ increased KLRG1 expression on NK cells. These findings suggest a role of KLRG1 in the pathogenesis of SLE and its potential as a biomarker for this disease.
Article
Oncology
Chiara Nicolazzo, Valentina Magri, Luca Marino, Francesca Belardinilli, Federica Di Nicolantonio, Gianluigi De Renzi, Salvatore Caponnetto, Michela De Meo, Giuseppe Giannini, Daniele Santini, Enrico Cortesi, Paola Gazzaniga
Summary: This study investigated the clinical and genomic features associated with RAS mutation clearance in RAS mutant mCRC patients who converted to RAS wild-type. The most commonly detected actionable mutations in neo-RAS wild-type were PIK3CA. Clearance of RAS mutations in ctDNA was associated with long-term improvement of overall survival.
FRONTIERS IN ONCOLOGY
(2023)
Review
Cell Biology
Rosa Molfetta, Sara Petillo, Marco Cippitelli, Rossella Paolini
Summary: SUMOylation is an important reversible modification that affects the function and stability of proteins. It has been discovered to play a role in the regulation of genomic stability and immune responses, particularly in natural killer (NK) cells. NK cells are innate immune cells that are crucial for host defense against viral infections and tumors. The expression of NK cell receptors and ligands on target cells is tightly regulated through post-translational modifications, including SUMOylation. This review focuses on the role of SUMOylation and related pathways in the biology of NK cells, with a special emphasis on their response against cancer. The potential use of selective inhibitors to enhance NK cell-mediated killing of tumor cells is also discussed.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Rossella Paolini, Rosa Molfetta
Summary: CD155, also known as the poliovirus receptor, is often overexpressed in tumors and promotes cell migration and proliferation. It plays an immunomodulatory role by binding to receptors on immune cells. DNAM-1 is involved in anti-tumor immune surveillance, while TIGIT acts as an immune checkpoint receptor, counterbalancing DNAM-1. Targeting CD155 and enhancing DNAM-1 function are promising therapeutic approaches, and clinical trials for anti-TIGIT treatment are already underway.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Sara Petillo, Elena Sproviero, Luisa Loconte, Lorenzo Cuollo, Alessandra Zingoni, Rosa Molfetta, Cinzia Fionda, Alessandra Soriani, Cristina Cerboni, Maria Teresa Petrucci, Francesca Fazio, Rossella Paolini, Angela Santoni, Marco Cippitelli
Summary: Natural Killer (NK) cells play an important regulatory role in the development of hematological malignancies, and their suppressor activity against Multiple Myeloma (MM) cells has been confirmed in multiple studies. Dysfunctions in NK cell effector activities and changes in NK cell subset distribution have been observed in MM patients, and these are correlated with disease staging.
CELL DEATH & DISEASE
(2023)
Article
Cell Biology
Rosa Molfetta, Mario Lecce, Nadia D. Milito, Erisa Putro, Giuseppe Pietropaolo, Caterina Marangio, Gianluca Scarno, Marta Moretti, Enrico De Smaele, Tiziana Santini, Giovanni Bernardini, Giuseppe Sciume, Angela Santoni, Rossella Paolini
Summary: Mast cells (MCs) are innate immune cells that play a multifaceted role in the tumor microenvironment (TME). Recent studies have shown that MCs contribute to the transition from chronic inflammation to cancer. However, MC-derived mediators can either promote tumor progression or exert anti-tumorigenic effects, depending on the microenvironmental stimuli. This study focused on a specific subset of MCs in a murine model of colitis-associated colorectal cancer and found that these tumor-associated MCs have a connective tissue phenotype and release interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. The presence of high levels of stem cell factor (SCF) and IL-33 in the tumor was found to shape the MC phenotype and promote the secretion of pro-inflammatory cytokines. This study highlights the importance of understanding the role of specific MC subsets in tumor progression.
CELL DEATH & DISEASE
(2023)
Review
Oncology
Rossella Paolini, Rosa Molfetta
Summary: The immune system utilizes various innate and adaptive cells to counteract tumor growth by detecting and eliminating abnormal cells. Natural killer (NK) cells, a part of the innate immune system, are able to distinguish cancerous cells from normal cells through the expression of activating and inhibitory receptors. DNAM-1 is an activating receptor that recognizes PVR and Nectin2 adhesion molecules, frequently found on the surface of cancer cells, and plays a central role in tumor recognition. However, the inhibitory receptors that also recognize PVR and Nectin2 are upregulated in the tumor microenvironment, leading to NK cell hypo-functionality. This review focuses on the potential molecular mechanisms responsible for the impairment of DNAM-1 functionality during tumor progression and discusses therapeutic approaches to reverse DNAM-1 dysfunction and NK cell hypo-responsiveness.
Article
Immunology
Cristina Capuano, Davide De Federicis, Daniel Ciuti, Ombretta Turriziani, Antonio Angeloni, Emanuela Anastasi, Giuseppe Giannini, Francesca Belardinilli, Rosa Molfetta, Domenico Alvaro, Gabriella Palmieri, Ricciarda Galandrini
Summary: This study demonstrates a durable downmodulation of CD16 levels and antibody-dependent NK cell functions after SARS-CoV-2 heterologous vaccination, and highlights the impact of genetic and environmental host-related factors in modulating NK cell susceptibility to post-vaccinal Fc-dependent functional impairment.
FRONTIERS IN IMMUNOLOGY
(2023)