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Article ; Online: Y

Rivoltini, Licia / Bhoori, Sherrie / Camisaschi, Chiara / Bergamaschi, Laura / Lalli, Luca / Frati, Paola / Citterio, Davide / Castelli, Chiara / Mazzaferro, Vincenzo

Gut

2022 Volume 72, Issue 2, Page(s) 406–407

MeSH term(s)	Humans ; Carcinoma, Hepatocellular/radiotherapy ; Liver Neoplasms/radiotherapy ; Embolization, Therapeutic ; Immunotherapy
Language	English
Publishing date	2022-05-04
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gutjnl-2021-326869
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Article ; Online: Multistep tumor genetic evolution and changes in immunogenicity trigger immune-mediated disease eradication in stage IV melanoma: lessons from a single case.

Vallacchi, Viviana / Vergani, Elisabetta / Cossa, Mara / Gargiuli, Chiara / Busico, Adele / Devecchi, Andrea / Dugo, Matteo / Bergamaschi, Laura / De Cecco, Loris / Cavalieri, Stefano / Valeri, Barbara / Tamborini, Elena / Gallino, Gianfrancesco / Del Vecchio, Michele / Santinami, Mario / Sensi, Marialuisa / Rivoltini, Licia / Di Guardo, Lorenza / Rodolfo, Monica

Journal for immunotherapy of cancer

2024 Volume 12, Issue 1

Abstract: Durable remissions are observed in 10%-20% of treated patients with advanced metastatic melanoma but the factors associated with long-term complete clinical responses are largely unknown. Here, we report the molecular characteristics of tumor evolution ... ...

Abstract	Durable remissions are observed in 10%-20% of treated patients with advanced metastatic melanoma but the factors associated with long-term complete clinical responses are largely unknown. Here, we report the molecular characteristics of tumor evolution during disease progression along a 9-year clinical course in a patient with advanced disseminated melanoma who received different treatments, including trametinib, ipilimumab, radiation, vemurafenib, surgical tumor debulking and a second ipilimumab course, ultimately achieving complete long-term disease remission.Longitudinal analyses of therapies-resistant metastatic tumors revealed the effects of different treatments on tumor's microenvironment and immunogenicity, ultimately creating a milieu favorable to immunotherapy response. Monitoring of the temporal dynamics of T cells by analysis of the T cell receptor (TCR) repertoire in the tumor and peripheral blood during disease evolution indicated that T-cell clones with common TCR rearrangements, present at low levels at baseline, were maintained and expanded after immunotherapy, and that TCR diversity increased. Analysis of genetic, molecular, and cellular components of the tumor depicted a multistep process in which treatment with kinase inhibitors strongly conditioned the immune microenvironment creating an inflamed milieu converting cold into hot tumors, while ipilimumab impacted and increased the TCR repertoire, a requirement for tumor rejection.Since the optimal sequencing of treatment with antibodies targeting immune checkpoints and kinase inhibitors for advanced melanoma is still clinically debated, this case indicates that immunotherapy success is possible even after progression on targeted therapy.
MeSH term(s)	Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Ipilimumab/therapeutic use ; Vemurafenib ; T-Lymphocytes/pathology ; Receptors, Antigen, T-Cell/therapeutic use ; Tumor Microenvironment
Chemical Substances	Ipilimumab ; Vemurafenib (207SMY3FQT) ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2024-01-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-007612
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Article ; Online: Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19.

Hanson, Aimee L / Mulè, Matthew P / Ruffieux, Hélène / Mescia, Federica / Bergamaschi, Laura / Pelly, Victoria S / Turner, Lorinda / Kotagiri, Prasanti / Göttgens, Berthold / Hess, Christoph / Gleadall, Nicholas / Bradley, John R / Nathan, James A / Lyons, Paul A / Drakesmith, Hal / Smith, Kenneth G C

Nature immunology

2024 Volume 25, Issue 3, Page(s) 471–482

Abstract: Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one ... ...

Abstract	Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1-3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.
MeSH term(s)	Humans ; Iron ; Erythropoiesis ; COVID-19 ; SARS-CoV-2 ; Research Personnel ; Disease Progression
Chemical Substances	Iron (E1UOL152H7)
Language	English
Publishing date	2024-03-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-024-01754-8
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Article ; Online: Extracellular vesicles in anti-tumor immunity.

Vergani, Elisabetta / Daveri, Elena / Vallacchi, Viviana / Bergamaschi, Laura / Lalli, Luca / Castelli, Chiara / Rodolfo, Monica / Rivoltini, Licia / Huber, Veronica

Seminars in cancer biology

2021 Volume 86, Issue Pt 1, Page(s) 64–79

Abstract: To what extent extracellular vesicles (EVs) can impact anti-tumor immune responses has only started to get unraveled. Their nanometer dimensions, their growing number of subtypes together with the difficulties in defining their origin hamper their ... ...

Abstract	To what extent extracellular vesicles (EVs) can impact anti-tumor immune responses has only started to get unraveled. Their nanometer dimensions, their growing number of subtypes together with the difficulties in defining their origin hamper their investigation. The existence of tumor cell lines facilitated advance in cancer EV understanding, while capturing information about phenotypes and functions of immune cell EVs in this context is more complex. The advent of immunotherapy with immune checkpoint inhibitors has further deepened the need to dissect the impact of EVs during immune activation and response, not least to contribute unraveling and preventing the generation of resistance occurring in the majority of patients. Here we discuss the factors that influence anddrive the immune response in cancer patients in the context of cancer therapeutics and the roles or possible functions that EVs can have in this scenario. With immune cell-derived EVs as leitmotiv, we will journey from EV discovery and subtypes through physiological and pathological functions, from similarities with tumor EVs to measures to revert detrimental consequences on immune responses to cancer.
MeSH term(s)	Humans ; Extracellular Vesicles/metabolism ; Immunotherapy ; Immunity ; Cell Line, Tumor
Language	English
Publishing date	2021-09-09
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1033980-2
ISSN	1096-3650 ; 1044-579X
ISSN (online)	1096-3650
ISSN	1044-579X
DOI	10.1016/j.semcancer.2021.09.004
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Article ; Online: Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor.

Ricciardiello, Francesca / Bergamaschi, Laura / De Vitto, Humberto / Gang, Yang / Zhang, Taiping / Palorini, Roberta / Chiaradonna, Ferdinando

Cells

2021 Volume 10, Issue 2

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death and the search for a resolutive therapy is still a challenge. Since KRAS is commonly mutated in PDAC and is one of the main drivers of PDAC progression, its inhibition ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death and the search for a resolutive therapy is still a challenge. Since KRAS is commonly mutated in PDAC and is one of the main drivers of PDAC progression, its inhibition should be a key strategy for treatment, especially considering the recent development of specific KRAS inhibitors. Nevertheless, the effects of KRAS inhibition can be increased through the co-inhibition of other nodes important for cancer development. One of them could be the hexosamine biosynthetic pathway (HBP), whose enhancement is considered fundamental for PDAC. Here, we demonstrate that PDAC cells expressing oncogenic KRAS, owing to an increase in the HBP flux, become strongly reliant on HBP for both proliferation and survival. In particular, upon treatment with two different compounds, 2-deoxyglucose and FR054, inhibiting both HBP and protein
MeSH term(s)	Adenocarcinoma/drug therapy ; Adenocarcinoma/pathology ; Animals ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/pathology ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Smegmamorpha
Language	English
Publishing date	2021-02-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10020431
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Article ; Online: Distinction of early complement classical and lectin pathway activation

Hurler, Lisa / Toonen, Erik J M / Kajdácsi, Erika / van Bree, Bregje / Brandwijk, Ricardo J M G E / de Bruin, Wieke / Lyons, Paul A / Bergamaschi, Laura / Sinkovits, György / Cervenak, László / Würzner, Reinhard / Prohászka, Zoltán

Frontiers in immunology

2022 Volume 13, Page(s) 1039765

Abstract: The most commonly used markers to assess complement activation are split products that are produced through activation of all three pathways and are located downstream of C3. In contrast, C4d derives from the cleavage of C4 and indicates either classical ...

Abstract	The most commonly used markers to assess complement activation are split products that are produced through activation of all three pathways and are located downstream of C3. In contrast, C4d derives from the cleavage of C4 and indicates either classical (CP) or lectin pathway (LP) activation. Although C4d is perfectly able to distinguish between CP/LP and alternative pathway (AP) activation, no well-established markers are available to differentiate between early CP and LP activation. Active enzymes of both pathways (C1s/C1r for the CP, MASP-1/MASP-2 for the LP) are regulated by C1 esterase inhibitor (C1-INH) through the formation of covalent complexes. Aim of this study was to develop validated immunoassays detecting C1s/C1-INH and MASP-1/C1-INH complex levels. Measurement of the complexes reveals information about the involvement of the respective pathways in complement-mediated diseases. Two sandwich ELISAs detecting C1s/C1-INH and MASP-1/C1-INH complex were developed and tested thoroughly, and it was investigated whether C1s/C1-INH and MASP-1/C1-INH complexes could serve as markers for either early CP or LP activation. In addition, a reference range for these complexes in healthy adults was defined, and the assays were clinically validated utilizing samples of 414 COVID-19 patients and 96 healthy controls. The immunoassays can reliably measure C1s/C1-INH and MASP-1/C1-INH complex concentrations in EDTA plasma from healthy and diseased individuals. Both complex levels are increased in serum when activated with zymosan, making them suitable markers for early classical and early lectin pathway activation. Furthermore, measurements of C1-INH complexes in 96 healthy adults showed normally distributed C1s/C1-INH complex levels with a physiological concentration of 1846 ± 1060 ng/mL (mean ± 2SD) and right-skewed distribution of MASP-1/C1-INH complex levels with a median concentration of 36.9 (13.18 - 87.89) ng/mL (2.5-97.5 percentile range), while levels of both complexes were increased in COVID-19 patients (p<0.0001). The newly developed assays measure C1-INH complex levels in an accurate way. C1s/C1-INH and MASP-1/C1-INH complexes are suitable markers to assess early classical and lectin pathway activation. An initial reference range was set and first studies showed that these markers have added value for investigating and unraveling complement activation in human disease.
MeSH term(s)	Adult ; Humans ; Complement C1 Inhibitor Protein ; Complement System Proteins ; COVID-19/diagnosis ; Lectins ; Mannose-Binding Protein-Associated Serine Proteases/metabolism ; Enzyme-Linked Immunosorbent Assay
Chemical Substances	Complement C1 Inhibitor Protein ; Complement System Proteins (9007-36-7) ; Lectins ; Mannose-Binding Protein-Associated Serine Proteases (EC 3.4.21.-)
Language	English
Publishing date	2022-11-04
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.1039765
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Article ; Online: Proteomic analysis of circulating immune cells identifies cellular phenotypes associated with COVID-19 severity.

Potts, Martin / Fletcher-Etherington, Alice / Nightingale, Katie / Mescia, Federica / Bergamaschi, Laura / Calero-Nieto, Fernando J / Antrobus, Robin / Williamson, James / Parsons, Harriet / Huttlin, Edward L / Kingston, Nathalie / Göttgens, Berthold / Bradley, John R / Lehner, Paul J / Matheson, Nicholas J / Smith, Kenneth G C / Wills, Mark R / Lyons, Paul A / Weekes, Michael P

Cell reports

2023 Volume 42, Issue 6, Page(s) 112613

Abstract: Certain serum proteins, including C-reactive protein (CRP) and D-dimer, have prognostic value in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, these factors are non-specific, providing limited mechanistic ... ...

Abstract	Certain serum proteins, including C-reactive protein (CRP) and D-dimer, have prognostic value in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, these factors are non-specific, providing limited mechanistic insight into the peripheral blood mononuclear cell (PBMC) populations that drive the pathogenesis of severe COVID-19. To identify cellular phenotypes associated with disease, we performed a comprehensive, unbiased analysis of total and plasma-membrane PBMC proteomes from 40 unvaccinated individuals with SARS-CoV-2, spanning the whole disease spectrum. Combined with RNA sequencing (RNA-seq) and flow cytometry from the same donors, we define a comprehensive multi-omic profile for each severity level, revealing that immune-cell dysregulation progresses with increasing disease. The cell-surface proteins CEACAMs1, 6, and 8, CD177, CD63, and CD89 are strongly associated with severe COVID-19, corresponding to the emergence of atypical CD3
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Leukocytes, Mononuclear ; Proteomics ; Phenotype
Language	English
Publishing date	2023-05-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112613
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Article ; Online: A patient-centric modeling framework captures recovery from SARS-CoV-2 infection.

Nature immunology

2023 Volume 24, Issue 2, Page(s) 349–358

Abstract: The biology driving individual patient responses to severe acute respiratory syndrome coronavirus 2 infection remains ill understood. Here, we developed a patient-centric framework leveraging detailed longitudinal phenotyping data and covering a year ... ...

Abstract	The biology driving individual patient responses to severe acute respiratory syndrome coronavirus 2 infection remains ill understood. Here, we developed a patient-centric framework leveraging detailed longitudinal phenotyping data and covering a year after disease onset, from 215 infected individuals with differing disease severities. Our analyses revealed distinct 'systemic recovery' profiles, with specific progression and resolution of the inflammatory, immune cell, metabolic and clinical responses. In particular, we found a strong inter-patient and intra-patient temporal covariation of innate immune cell numbers, kynurenine metabolites and lipid metabolites, which highlighted candidate immunologic and metabolic pathways influencing the restoration of homeostasis, the risk of death and that of long COVID. Based on these data, we identified a composite signature predictive of systemic recovery, using a joint model on cellular and molecular parameters measured soon after disease onset. New predictions can be generated using the online tool http://shiny.mrc-bsu.cam.ac.uk/apps/covid-19-systemic-recovery-prediction-app , designed to test our findings prospectively.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Post-Acute COVID-19 Syndrome ; Kynurenine ; Patient-Centered Care
Chemical Substances	Kynurenine (343-65-7)
Language	English
Publishing date	2023-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-022-01380-2
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis.

Journal of autoimmunity

2023 Volume 142, Page(s) 103133

Abstract: B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell ... ...

Abstract	B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27
MeSH term(s)	Humans ; NF-kappa B/metabolism ; Signal Transduction ; B-Lymphocytes/metabolism ; NF-kappaB-Inducing Kinase ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/metabolism
Chemical Substances	NF-kappa B ; NF-kappaB-Inducing Kinase (EC 2.7.11.25)
Language	English
Publishing date	2023-11-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639452-8
ISSN	1095-9157 ; 0896-8411
ISSN (online)	1095-9157
ISSN	0896-8411
DOI	10.1016/j.jaut.2023.103133
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Article ; Online: Molecular Determinants of Soft Tissue Sarcoma Immunity: Targets for Immune Intervention.

Tazzari, Marcella / Bergamaschi, Laura / De Vita, Alessandro / Collini, Paola / Barisella, Marta / Bertolotti, Alessia / Ibrahim, Toni / Pasquali, Sandro / Castelli, Chiara / Vallacchi, Viviana

International journal of molecular sciences

2021 Volume 22, Issue 14

Abstract: Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic ... ...

Abstract	Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic strategies urgently needed. From a molecular point of view, STSs can be classified as translocation-related and those with a heavily rearranged genotype. Although only the latter display an increased mutational burden, molecular profiles suggestive of an "immune hot" tumor microenvironment are observed across STS histologies, and response to immunotherapy has been reported in both translocation-related and genetic complex STSs. These data reinforce the notion that immunity in STSs is multifaceted and influenced by both genetic and epigenetic determinants. Cumulative evidence indicates that a fine characterization of STSs at different levels is required to identify biomarkers predictive of immunotherapy response and to discover targetable pathways to switch on the immune sensitivity of "immune cold" tumors. In this review, we will summarize recent findings on the interplay between genetic landscape, molecular profiling and immunity in STSs. Immunological and molecular features will be discussed for their prognostic value in selected STS histologies. Finally, the local and systemic immunomodulatory effects of the targeted drugs imatinib and sunitinib will be discussed.
MeSH term(s)	Animals ; Biomarkers, Tumor/antagonists & inhibitors ; Biomarkers, Tumor/immunology ; Gene Expression Regulation, Neoplastic ; Humans ; Immunotherapy/methods ; Molecular Targeted Therapy ; Sarcoma/drug therapy ; Sarcoma/immunology ; Sarcoma/pathology ; Tumor Microenvironment/immunology
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2021-07-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22147518
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