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Human NK cells: surface receptors, inhibitory checkpoints, and translational applications

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Cellular & Molecular Immunology 2019年第5期16卷 430-441页

作者： Simona Sivori Paola Vacca Genny Del Zotto Enrico Munari Maria Cristina Mingari Lorenzo Moretta Department of Experimental Medicine(DIMES)and Centre of Excellence for Biomedical Research(CEBR) University of GenoaGenoaItaly Department of Immunology IRCCS Bambino GesuChildren’s HospitalRomeItaly Department of Research and Diagnostics Istituto G.GasliniGenoaItaly Department of Diagnostics and Public Health University of VeronaVeronaItaly Department of Pathology Sacro Cuore Don CalabriaNegrarVRItaly UOC Immunologia IRCCS Ospedale Policlinico San Martino GenovaGenoaItaly

NK cells play important roles in innate defenses against viruses and in the control of tumor growth and *** regulation/induction of NK cell function is mediated by an array of activating or inhibitory surface *** humans,major activating receptors involved in target cell killing are the natural cytotoxicity receptors(NCRs)and *** receptors recognize ligands that are overexpressed or expressed de novo upon cell stress,viral infection,or tumor *** HLA-class I-specific inhibitory receptors,including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E,constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy *** receptors such as PD-1,primarily expressed by activated T lymphocytes,are important inhibitory checkpoints of immune responses that ensure T-cell ***-1 also may be expressed by NK cells in cancer *** PD-1 ligand(PD-L1)may be expressed by different tumors,PD-1/PD-L1 interactions inactivate both T and NK ***,the reliable evaluation of PD-L1 expression in tumors has become a major issue to select patients who may benefit from therapy with mAbs disrupting PD-1/PD-L1 ***,NKG2A was revealed to be an important checkpoint controlling both NK and T-cell *** most tumors express HLA-E,mAbs targeting NKG2A has been used alone or in combination with other therapeutic mAbs targeting PD-1 or tumor antigens(e.g.,EGFR),with encouraging *** translational value of NK cells and their receptors is evidenced by the extraordinary therapeutic success of haploidentical HSCT to cure otherwise fatal high-risk leukemias.

关键词： Human NK cells NK receptors Inhibitory checkpoints Immunotherapy

Implications of metabolism-driven myeloid dysfunctions in cancer therapy

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Cellular & Molecular Immunology 2021年第4期18卷 829-841页

作者： Laura Strauss Valentina Guarneri Alessandra Gennari Antonio Sica Department of Immunopharmacology and Immuno Oncology EMD Serono Research&Development InstituteInc.80119545A Middlesex TurnpikeBillericaMA 01821USA Department of Surgery Oncology and GastroenterologyUniversity of PadovaPadovaItaly Veneto Institute of Oncology-IRCCS PaduaItalyPadovaItaly Division of Oncology Department of Translational MedicineUniversity of Eastern PiedmontNovaraItaly Department of Pharmaceutical Sciences University of Eastern PiedmontA.Avogadrovia Bovio 6NovaraItaly Humanitas Clinical and Research Center IRCCSVia Manzoni 56RozzanoMilanItaly

Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid *** chronic inflammatory states,including cancer,this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils,macrophages,and dendritic cells(DCs),thus giving rise to a decline in the antitumor effector lymphoid ***-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors,resulting in unresolved and chronic *** pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool,which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor ***,persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer,as well as to the severity of a broad range of diseases,including metabolic syndrome and autoimmune and infectious *** aims of this review are to(1)define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients,(2)discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes,and(3)explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor *** propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects(irAEs)for current therapeutic strategies,including immune checkpoint inhibitor(ICI)therapy.

关键词： Myelopoiesis Tumor-associated macrophages Myeloid-derived suppressor cells Metabolism Cancer therapy

Genetic predisposition to pancreatic cancer

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World Journal of Gastroenterology 2014年第31期20卷 10778-10789页

作者： Paola Ghiorzo Department of Internal Medicine and Medical Specialties University of Genoa and IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazioanle per la Ricerca sul Cancro 16132 Genoa Italy

Pancreatic adenocarcinoma(PC) is the most deadly of the common cancers. Owing to its rapid progression and almost certain fatal outcome, identifying individuals at risk and detecting early lesions are crucial to improve outcome. Genetic risk factors are believed to play a major role. Approximately 10% of PC is estimated to have familial inheritance. Several germline mutations have been found to be involved in hereditary forms of PC, including both familial PC(FPC) and PC as one of the manifestations of a hereditary cancer syndrome or other hereditary conditions. Although most of the susceptibility genes for FPC have yet to be identified, next-generation sequencing studies are likely to provide important insights. The risk of PC in FPC is sufficiently high to recommend screening of high-risk individuals; thus, defining such individuals appropriately is the key. Candidate genes have been described and patients considered for screening programs under research protocols should first be tested for presence of germline mutations in the BRCA2, PALB2 and ATM genes. In specific PC populations, including in Italy, hereditary cancer predisposition genes such as CDKN2 A also explain a considerable fraction of FPC.

关键词： Pancreatic adenocarcinoma Susceptibility genes CDKN2A Melanoma Hereditary cancer syndromes Screening

Inhibition of host immune response in colorectal cancer:Human leukocyte antigen-G and beyond

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World Journal of Gastroenterology 2014年第14期20卷 3778-3794页

作者： Marica Garziera Giuseppe Toffoli Experimental and Clinical Pharmacology Unit CRO Aviano National Cancer Institute 33081 Aviano Italy

Colorectal cancer (CRC) is one of the most diffuse cancers worldwide and is still a clinical burden. Increasing evidences associate CRC clinical outcome to immune contexture represented by adaptive immune cells. Their type, density and location are summarized in the Immune Score that has been shown to improve prognostic prediction of CRC patients. The non-classical MHC class I human leukocyte antigen-G (HLA-G), is a crucial tumor-driven immune escape molecule involved in immune tolerance. HLA-G and soluble counterparts are able to exert inhibitory functions by direct interactions with inhibitory receptors present on both innate cells such as natural killer cells, and adaptive immune cells as cytotoxic T and B lymphocytes. HLA-G may play a prominent role in CRC strategies to avoid host immunosurveillance. This review highlights the current knowledge on HLA-G contribution in CRC, in related inflammatory diseases and in other type of cancers and disorders. HLA-G genetic setting (specific haplotypes, genotypes and alleles frequencies) and association with circulating/soluble profiles was highlighted. HLA G prognostic and predictive value in CRC was investigated in order to define a novel prognostic immune biomarker in CRC.

关键词： Colorectal cancer Human leukocyte antigen-G Immune score T lymphocytes Untranslated regions

Exploitation of host clock gene machinery by hepatitis viruses B and C

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World Journal of Gastroenterology 2013年第47期19卷 8902-8909页

作者： Manlio Vinciguerra Gianluigi Mazzoccoli Claudia Piccoli Tiziana Tataranni Angelo Andriulli Valerio Pazienza Institute for Liver and Digestive Health Division of MedicineUniversity College London (UCL)London SW7 2AZUnited Kingdom Gastroenterology Unit IRCCS "Casa Sollievo della Sofferenza" Hospital71013 San Giovanni Rotondo (FG)Italy Department of Medical Sciences Division of Internal MedicineIRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza"71013 San Giovanni Rotondo (FG)Italy Department of Clinical and Experimental Medicine University of Foggia71100 FoggiaItaly Laboratory of Pre-Clinical and Translational Research IRCCSCentro di Riferimento Oncologico della Basilicata (CROB)85028 Rionero in Vulture (PZ)Italy

Many aspects of cellular physiology display circadian(approximately 24-h)*** of the circadian clock molecular circuitry is associated with human health derangements,including neurodegeneration,increased risk of cancer,cardiovascular diseases and the metabolic *** triggering hepatitis depend tightly on the host cell synthesis machinery for their own replication,survival and *** evidences support a link between the circadian clock circuitry and viruses’biological cycle within host ***,in vitro models for chronobiological studies of cells infected with viruses need to be *** establishment of such in vitro models would be helpful to better understand the link between the clock gene machinery and viral replication/viral persistence in order to develop specifically targeted therapeutic *** we review the recent literature dealing with the interplay between hepatitis B and C viruses and clock genes.

关键词： Hepatitis C virus Hepatitis B virus Antihepatitis therapy Clock genes Chronobiology

Identify multiple myeloma stem cells: Utopia?

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World Journal of Stem Cells 2015年第1期7卷 84-95页

作者： Ilaria Saltarella Aurelia Lamanuzzi Antonia Reale Angelo Vacca Roberto Ria Department of Biomedical Sciences and Human Oncology Section of Internal Medicine "G. Baccelli" University of Bari "Aldo Moro" Medical School Policlinico I-70124 Bari Italy

Multiple myeloma(MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells(CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activate stemness signaling(Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.

关键词： Bone marrow microenvironment Cancerstem cells Multiple myeloma Stem cells niche Stemness

Hip prosthetic loosening and periprosthetic osteolysis:A commentary

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World Journal of Orthopedics 2022年第6期13卷 574-577页

作者： Bengt Mjöberg Department of Orthopedics Lund UniversityLund SE-22100Sweden

Prosthetic loosening and periprosthetic osteolysis have been debated for decades,both in terms of the timing and nature of the triggering *** hypothesis of wear-particle-induced loosening states that wear particles cause a foreign-body response leading to periprosthetic osteolysis and ultimately to late prosthetic loosening,i.e.,that the osteolysis precedes the *** theory of early loosening,on the other hand,postulates that the loosening is already initiated during or shortly after surgery,i.e.,that the osteolysis is secondary to the *** commentary focuses on the causal relationship between prosthetic loosening and periprosthetic osteolysis.

关键词： Hip prosthesis Radiostereometric analysis Prosthesis failure Osteoclasts Bone resorption Alarmins

Liquid biopsy in lymphomas: a potential tool for refining diagnosis and disease monitoring

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Journal of Cancer Metastasis and Treatment 2019年第9期4卷 20-27页

作者： Riccardo Moia Chiara Favini Silvia Rasi Clara Deambrogi Valentina Ferri Mattia Schipani Sruthi Sagiraju Abdurraouf Mokhtar Mahmoud Ahad Ahmed Kodipad Ramesh Adhinaveni Andrea Patriarca Luca Nassi Gianluca Gaidano Division of Hematology Department of Translational Medicine University of Eastern Piedmont and Ospedale Maggiore della Carità Novara 28100 Italy

Liquid biopsy consists in a simple blood sampling that allows to analyze cell free DNA (cfDNA), containing specific genomic clues released by the tumor into the bloodstream. In this review, we shall focus on the analysis of cfDNA in lymphoma and, in particular, on its application in the genotyping and monitoring of two common types of B-cell lymphoma, i.e., diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). From a diagnostic standpoint and based upon the current international guidelines, lymphoma diagnosis has so far relied on the analysis of the tissue biopsy. From a molecular viewpoint, though, the tissue biopsy does not reflect the entire molecular heterogeneity of lymphomas. In fact, in an individual patient, lymph nodes at different anatomical sites, as well as different areas of the same lymph node, may show different genetic profiles. Consequently, molecular analysis of genomic DNA extracted from a single lymph node biopsy may not recapitulate the whole mutational landscape of the disease. Liquid biopsy may overcome this hurdle, since cfDNA is released by all tumoral cells and can reveal the entire molecular complexity of lymphomas. From a translational perspective, liquid biopsy may also be used to evaluate clonal evolution, response to therapy and minimal residual disease. Consistently, in DLBCL as well in cHL, the drop of the mutational burden during the treatment course provides complementary information to conventional imaging techniques. The integration of liquid biopsy with imaging techniques may prove useful for a better prediction of patients' outcome and for a better treatment tailoring.

关键词： Liquid biopsy lymphoma precision medicine

The multifaceted PDCD10/CCM3 gene

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Genes & Diseases 2021年第6期8卷 798-813页

作者： Mariaelena Valentino Elisabetta Dejana Matteo Malinverno The FIRC Institute of Molecular Oncology(IFOM) Milan1620139Italy Department of Oncology and Haemato-Oncology University of MilanMilan720122Italy Vascular Biology Department of ImmunologyGenetics and PathologyUppsala UniversityUppsalaSE-75105Sweden

The programmed cell death 10(PDCD10)gene was originally identified as an apoptosis-related gene,although it is now usually known as CCM3,as the third causative gene of cerebral cavernous malformation(CCM).CCM is a neurovascular disease that is characterized by vascular malformations and is associated with headaches,seizures,focal neurological deficits,and cerebral *** PDCD10/CCM3 protein has multiple subcellular localizations and interacts with several multi-protein complexes and signaling *** PDCD10/CCM3 governs many cellular functions,which include cell-to-cell junctions and cytoskeleton organization,cell proliferation and apoptosis,and exocytosis and *** its central role in the maintenance of homeostasis of the cell,dysregulation of PDCD10/CCM3 can result in a wide range of altered cell *** can lead to severe diseases,including CCM,cognitive disability,and several types of ***,we review the multifaceted roles of PDCD10/CCM3 in physiology and pathology,with a focus on its functions beyond CCM.

关键词： Cancer Cell signaling Cell-cycle Neurovascular unit PDCD10/CCM3