SUMOylation and related post-translational modifications in natural killer cell anti-cancer responses

SUMOylation is a reversible modification that involves the covalent attachment of small ubiquitin-like modifier (SUMO) to target proteins, leading to changes in their localization, function, stability, and interactor profile. SUMOylation and additional related post-translational modifications have emerged as important modulators of various biological processes, including regulation of genomic stability and immune responses. Natural killer (NK) cells are innate immune cells that play a critical role in host defense against viral infections and tumors. NK cells can recognize and kill infected or transformed cells without prior sensitization, and their activity is tightly regulated by a balance of activating and inhibitory receptors. Expression of NK cell receptors as well as of their specific ligands on target cells is finely regulated during malignant transformation through the integration of different mechanisms including ubiquitin- and ubiquitin-like post-translational modifications. Our review summarizes the role of SUMOylation and other related pathways in the biology of NK cells with a special emphasis on the regulation of their response against cancer. The development of novel selective inhibitors as useful tools to potentiate NK-cell mediated killing of tumor cells is also briefly discussed

Role of NF-κB Signaling in the Interplay between Multiple Myeloma and Mesenchymal Stromal Cells

Nuclear factor-κB (NF-κB) transcription factors play a key role in the pathogenesis of multiple myeloma (MM). The survival, proliferation and chemoresistance of malignant plasma cells largely rely on the activation of canonical and noncanonical NF-κB pathways. They are triggered by cancer-associated mutations or by the autocrine and paracrine production of cytokines and growth factors as well as direct interaction with cellular and noncellular components of bone marrow microenvironment (BM). In this context, NF-κB also significantly affects the activity of noncancerous cells, including mesenchymal stromal cells (MSCs), which have a critical role in disease progression. Indeed, NF-κB transcription factors are involved in inflammatory signaling that alters the functional properties of these cells to support cancer evolution. Moreover, they act as regulators and/or effectors of pathways involved in the interplay between MSCs and MM cells. The aim of this review is to analyze the role of NF-κB in this hematologic cancer, focusing on NF-κB-dependent mechanisms in tumor cells, MSCs and myeloma–mesenchymal stromal cell crosstalk

Role of NF-κB Signaling in the Interplay between Multiple Myeloma and Mesenchymal Stromal Cells

Nuclear factor-κB (NF-κB) transcription factors play a key role in the pathogenesis of multiple myeloma (MM). The survival, proliferation and chemoresistance of malignant plasma cells largely rely on the activation of canonical and noncanonical NF-κB pathways. They are triggered by cancer-associated mutations or by the autocrine and paracrine production of cytokines and growth factors as well as direct interaction with cellular and noncellular components of bone marrow microenvironment (BM). In this context, NF-κB also significantly affects the activity of noncancerous cells, including mesenchymal stromal cells (MSCs), which have a critical role in disease progression. Indeed, NF-κB transcription factors are involved in inflammatory signaling that alters the functional properties of these cells to support cancer evolution. Moreover, they act as regulators and/or effectors of pathways involved in the interplay between MSCs and MM cells. The aim of this review is to analyze the role of NF-κB in this hematologic cancer, focusing on NF-κB-dependent mechanisms in tumor cells, MSCs and myeloma–mesenchymal stromal cell crosstalk

NEDD8-activating enzyme inhibition potentiates the anti-myeloma activity of natural killer cells

Abstract Natural Killer (NK) cells act as important regulators in the development and progression of hematological malignancies and their suppressor activity against Multiple Myeloma (MM) cells has been confirmed in many studies. Significant changes in the distribution of NK cell subsets and dysfunctions of NK cell effector activities were described in MM patients and correlated with disease staging. Thus, restoring or enhancing the functionality of these effectors for the treatment of MM represents a critical need. Neddylation is a post-translational modification that adds a ubiquitin-like molecule, NEDD8, to the substrate protein. One of the outcomes is the activation of the Cullin Ring Ligases (CRLs), a class of ubiquitin-ligases that controls the degradation of about 20% of proteasome-regulated proteins. Overactivation of CRLs has been described in cancer and can lead to tumor growth and progression. Thus, targeting neddylation represents an attractive approach for cancer treatment. Our group has recently described how pharmacologic inhibition of neddylation increases the expression of the NKG2D activating receptor ligands, MICA and MICB, in MM cells, making these cells more susceptible to NK cell degranulation and killing. Here, we extended our investigation to the direct role of neddylation on NK cell effector functions exerted against MM. We observed that inhibition of neddylation enhanced NK cell-mediated degranulation and killing against MM cells and improved Daratumumab/Elotuzumab-mediated response. Mechanistically, inhibition of neddylation increased the expression of Rac1 and RhoA GTPases in NK cells, critical mediators for an efficient degranulation at the immunological synapse of cytotoxic lymphocytes, and augmented the levels of F-actin and perforin polarization in NK cells contacting target cells. Moreover, inhibition of neddylation partially abrogated TGFβ-mediated repression of NK cell effector activity. This study describes the role of neddylation on NK cell effector functions and highlights the positive immunomodulatory effects achieved by the inhibition of this pathway in MM

Evaluation of Flu Vaccination Coverage among Healthcare Workers during a 3 Years’ Study Period and Attitude towards Influenza and Potential COVID-19 Vaccination in the Context of the Pandemic

(1) Background: vaccination of healthcare workers (HCWs) against seasonal influenza is considered the most effective way to protect HCWs, ensure patient’s safety and to maintain essential health care services during influenza epidemics. With the present study we aimed to evaluate the efficacy of incremental bundles of measures implemented during the last three flu campaigns and to assess the attitudes towards influenza vaccination and a potential vaccine against COVID-19 among HCWs, in a large university hospital in Pisa, Italy. (2) Methods: We described measures implemented during 2018/2019, 2019/2020 and 2020/2021 and assessed their impact on flu vaccine coverage (VC) among employees and residents in Pisa university hospital. We considered sex, profession and ward to investigate differences in uptake. In addition, in 2020 a survey was developed and distributed to all employees to evaluate flu and COVID-19 vaccines attitudes. (3) Results: during the 2018/19 and 2019/20 flu campaigns the overall VC rate among HCWs was, respectively, 10.2% and 11.9%. In 2020/21 the overall VC rate jumped to 39.3% (+ 230.6%). Results from the survey indicated a more positive attitude towards flu vaccine as compared to COVID-19 vaccines among the 10.6% of the staff members who responded to the survey. In addition, 70.97% of HCWs totally agreed that being vaccinated against influenza would be more important than the previous years because of COVID-19 emergency. (4) Conclusions: a significant increase in VC was observed in 2020/21, especially among those sub-groups with consistently lower uptake in previous years. The COVID-19 pandemic positively influenced flu vaccination uptake during the 2020/21 season

“Reflecting on Style and Surtitles: The Case of Falstaff by Giuseppe Verdi”

The aim of this work is to integrate a more traditional description of what opera surtitling is – a professional practice first and foremost, relatively recently turned into the object of academic research, which should deserve further attention by scholars and professionals alike, also due to its strategic importance in terms of social inclusion and accessibility – with a reflection on style in translation: in other words, this contribution intends to verify whether, and to what extent, opera surtitles should be “condemned” to be a highly summarised and abridged form of translation, or whether, instead, they can be respectful and accurate in reproducing the stylistic features and rhetorical effects of the original libretto, in spite of their brevity and conciseness. The selection of the linguistic materials fell on Falstaff by Giuseppe Verdi, based on Arrigo Boito’s libretto because, due to the sparking creativity and huge variety of his lexical and stylistic choices, producing English surtitles from this libretto is a stimulating task which requires not only a sound professional background, but also a refined artistic sensibility. Therefore, many significant examples are available to those who want to investigate such issues as surtitling and stylistics, since these surtitles are a successful illustration of a stylistically-oriented translation

CD38 restrains the activity of extracellular cGAMP in a model of multiple myeloma

Summary: 2′3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) is the endogenous agonist of STING; as such, cGAMP has powerful immunostimulatory activity, due to its capacity to stimulate type I interferon-mediated immunity. Recent evidence indicates that cancer cells, under certain conditions, can release cGAMP extracellularly, a phenomenon currently considered important for therapeutic responses and tumor rejection. Nonetheless, the mechanisms that regulate cGAMP activity in the extracellular environment are still largely unexplored.In this work, we collected evidence demonstrating that CD38 glycohydrolase can inhibit extracellular cGAMP activity through its direct binding.We firstly used different cell lines and clinical samples to demonstrate a link between CD38 and extracellular cGAMP activity; we then performed extensive in silico molecular modeling and cell-free biochemical assays to show a direct interaction between the catalytic pocket of CD38 and cGAMP. Altogether, our findings expand the current knowledge about the regulation of cGAMP activity

Impact on NK cell functions of acute versus chronic exposure to extracellular vesicle-associated MICA. Dual role in cancer immunosurveillance

Natural killer (NK) cells are innate cytotoxic lymphocytes that play a key role in cancer immunosurveillance thanks to their ability to recognize and kill cancer cells. NKG2D is an activating receptor that binds to MIC and ULBP molecules typically induced on damaged, transformed or infected cells. The release of NKG2D ligands (NKG2DLs) in the extracellular milieu through protease-mediated cleavage or by extracellular vesicle (EV) secretion allows cancer cells to evade NKG2D-mediated immunosurveillance. In this work, we investigated the immunomodulatory properties of the NKG2D ligand MICA*008 associated to distinct populations of EVs (i.e., small extracellular vesicles [sEVs] and medium size extracellular vesicles [mEVs]). By using as model a human MICA*008-transfected multiple myeloma (MM) cell line, we found that this ligand is present on both vesicle populations. Interestingly, our findings reveal that NKG2D is specifically involved in the uptake of vesicles expressing its cognate ligand. We provide evidence that MICA*008-expressing sEVs and mEVs are able on one hand to activate NK cells but, following prolonged stimulation induce a sustained NKG2D downmodulation leading to impaired NKG2D-mediated functions. Moreover, our findings show that MICA*008 can be transferred by vesicles to NK cells causing fratricide. Focusing on MM as a clinically and biologically relevant-model of tumour-NK cell interactions, we found enrichment of EVs expressing MICA in the bone marrow of a cohort of patients. All together our results suggest that the accumulation of NKG2D ligands associated to vesicles in the tumour microenvironment could favour the suppression of NK cell activity either by NKG2D downmodulation or by fratricide of NK cell dressed with EV-derived NKG2D ligands