24 results on '"Klas Karre"'
Search Results
2. Supplementary Table 3. from Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway
- Author
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Ennio Carbone, Matilde Todaro, Paolo A. Ascierto, Klas Karre, Alessandro Moretta, Aroldo Rizzo, Elio Gulletta, Francesco Saverio Costanzo, Valter Agosti, Genny Del Zotto, Silvia Pesce, Emanuela Marcenaro, Rossana Tallerico, Antonio M. Grimaldi, Emilia Dora Giovannone, Cinzia Garofalo, Domenico Mallardo, Gabriele Madonna, Mariaelena Capone, Tiziana Apuzzo, Valeria Ventura, Alice Turdo, and Costanza Maria Cristiani
- Abstract
Immune, biological and clinical variables used to built OPLS-DA model
- Published
- 2023
3. Supplementary Table 1. from Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway
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Ennio Carbone, Matilde Todaro, Paolo A. Ascierto, Klas Karre, Alessandro Moretta, Aroldo Rizzo, Elio Gulletta, Francesco Saverio Costanzo, Valter Agosti, Genny Del Zotto, Silvia Pesce, Emanuela Marcenaro, Rossana Tallerico, Antonio M. Grimaldi, Emilia Dora Giovannone, Cinzia Garofalo, Domenico Mallardo, Gabriele Madonna, Mariaelena Capone, Tiziana Apuzzo, Valeria Ventura, Alice Turdo, and Costanza Maria Cristiani
- Abstract
Primary melanoma cell lines
- Published
- 2023
4. Supplementary Table 2. from Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway
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Ennio Carbone, Matilde Todaro, Paolo A. Ascierto, Klas Karre, Alessandro Moretta, Aroldo Rizzo, Elio Gulletta, Francesco Saverio Costanzo, Valter Agosti, Genny Del Zotto, Silvia Pesce, Emanuela Marcenaro, Rossana Tallerico, Antonio M. Grimaldi, Emilia Dora Giovannone, Cinzia Garofalo, Domenico Mallardo, Gabriele Madonna, Mariaelena Capone, Tiziana Apuzzo, Valeria Ventura, Alice Turdo, and Costanza Maria Cristiani
- Abstract
Antibodies used for flow cytometry analysis
- Published
- 2023
5. Data from Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway
- Author
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Ennio Carbone, Matilde Todaro, Paolo A. Ascierto, Klas Karre, Alessandro Moretta, Aroldo Rizzo, Elio Gulletta, Francesco Saverio Costanzo, Valter Agosti, Genny Del Zotto, Silvia Pesce, Emanuela Marcenaro, Rossana Tallerico, Antonio M. Grimaldi, Emilia Dora Giovannone, Cinzia Garofalo, Domenico Mallardo, Gabriele Madonna, Mariaelena Capone, Tiziana Apuzzo, Valeria Ventura, Alice Turdo, and Costanza Maria Cristiani
- Abstract
Immune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T-cell subpopulations from melanoma patients. The patients' immune profiles suggested that melanoma progression leads to changes in peripheral blood NK and T-cell subsets. Stage IV melanoma was characterized by an increased frequency of CCR7+CD56bright NK cells as well as high serum concentrations of the CCR7 ligand CCL19. CCR7 expression and CCL19 secretion were also observed in melanoma cell lines. The CCR7+ melanoma cell subpopulation coexpressed PD-L1 and Galectin-9 and had stemness properties. Analysis of melanoma-derived cancer stem cells (CSC) showed high CCR7 expression; these CSCs were efficiently recognized and killed by NK cells. An accumulation of CCR7+, PD-L1+, and Galectin-9+ melanoma cells in melanoma metastases was demonstrated ex vivo. Altogether, our data identify biomarkers that may mark a CCR7-driven metastatic melanoma pathway.
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- 2023
6. Supplementary Figure 1. Immunomodulatory ligands on melanoma cells. from Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway
- Author
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Ennio Carbone, Matilde Todaro, Paolo A. Ascierto, Klas Karre, Alessandro Moretta, Aroldo Rizzo, Elio Gulletta, Francesco Saverio Costanzo, Valter Agosti, Genny Del Zotto, Silvia Pesce, Emanuela Marcenaro, Rossana Tallerico, Antonio M. Grimaldi, Emilia Dora Giovannone, Cinzia Garofalo, Domenico Mallardo, Gabriele Madonna, Mariaelena Capone, Tiziana Apuzzo, Valeria Ventura, Alice Turdo, and Costanza Maria Cristiani
- Abstract
Frequency and expression of the indicated molecules on CCR7- and CCR7+ melanoma cells.
- Published
- 2023
7. Overall survival of patients stratified for CCL19 serum concentration. from Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway
- Author
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Ennio Carbone, Matilde Todaro, Paolo A. Ascierto, Klas Karre, Alessandro Moretta, Aroldo Rizzo, Elio Gulletta, Francesco Saverio Costanzo, Valter Agosti, Genny Del Zotto, Silvia Pesce, Emanuela Marcenaro, Rossana Tallerico, Antonio M. Grimaldi, Emilia Dora Giovannone, Cinzia Garofalo, Domenico Mallardo, Gabriele Madonna, Mariaelena Capone, Tiziana Apuzzo, Valeria Ventura, Alice Turdo, and Costanza Maria Cristiani
- Abstract
Kaplan-Meier survival curves in 9 patients with low and 13 with high CCL19 serum concentration.
- Published
- 2023
8. CSCs characterization. from Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway
- Author
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Ennio Carbone, Matilde Todaro, Paolo A. Ascierto, Klas Karre, Alessandro Moretta, Aroldo Rizzo, Elio Gulletta, Francesco Saverio Costanzo, Valter Agosti, Genny Del Zotto, Silvia Pesce, Emanuela Marcenaro, Rossana Tallerico, Antonio M. Grimaldi, Emilia Dora Giovannone, Cinzia Garofalo, Domenico Mallardo, Gabriele Madonna, Mariaelena Capone, Tiziana Apuzzo, Valeria Ventura, Alice Turdo, and Costanza Maria Cristiani
- Abstract
Negative controls for CD44, CD271, ABCB5, and CD166 antibodies on melanoma CSCs.
- Published
- 2023
9. Accumulation of Circulating CCR7
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Costanza Maria, Cristiani, Alice, Turdo, Valeria, Ventura, Tiziana, Apuzzo, Mariaelena, Capone, Gabriele, Madonna, Domenico, Mallardo, Cinzia, Garofalo, Emilia Dora, Giovannone, Antonio M, Grimaldi, Rossana, Tallerico, Emanuela, Marcenaro, Silvia, Pesce, Genny, Del Zotto, Valter, Agosti, Francesco Saverio, Costanzo, Elio, Gulletta, Aroldo, Rizzo, Alessandro, Moretta, Klas, Karre, Paolo A, Ascierto, Matilde, Todaro, and Ennio, Carbone
- Subjects
Killer Cells, Natural ,Male ,Receptors, CCR7 ,Galectins ,Neoplastic Stem Cells ,Chemokine CCL19 ,Cytokines ,Humans ,Female ,Melanoma ,B7-H1 Antigen ,Coculture Techniques ,Cell Line - Abstract
Immune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T-cell subpopulations from melanoma patients. The patients' immune profiles suggested that melanoma progression leads to changes in peripheral blood NK and T-cell subsets. Stage IV melanoma was characterized by an increased frequency of CCR7
- Published
- 2018
10. PD-1 expression on mouse intratumoral NK cells and its effects on NK cell phenotype
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Arnika K. Wagner, Nadir Kadri, Chris Tibbitt, Koen van de Ven, Sunitha Bagawath-Singh, Denys Oliinyk, Eric LeGresley, Nicole Campbell, Stephanie Trittel, Peggy Riese, Ulf Ribacke, Tatyana Sandalova, Adnane Achour, Klas Kärre, and Benedict J. Chambers
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Immunology ,Components of the immune system ,Cancer ,Transcriptomics ,Science - Abstract
Summary: Although PD-1 was shown to be a hallmark of T cells exhaustion, controversial studies have been reported on the role of PD-1 on NK cells. Here, we found by flow cytometry and single cell RNA sequencing analysis that PD-1 can be expressed on MHC class I-deficient tumor-infiltrating NK cells in vivo. We also demonstrate distinct alterations in the phenotype of PD-1-deficient NK cells and a more mature phenotype which might reduce their capacity to migrate and kill in vivo. Tumor-infiltrating NK cells that express PD-1 were highly associated with the expression of CXCR6. Furthermore, our results demonstrate that PD-L1 molecules in membranes of PD-1-deficient NK cells migrate faster than in NK cells from wild-type mice, suggesting that PD-1 and PD-L1 form cis interactions with each other on NK cells. These data demonstrate that there may be a role for the PD-1/PD-L1 axis in tumor-infiltrating NK cells in vivo.
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- 2022
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11. Towards a cancer mission in Horizon Europe: recommendations
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Anton Berns, Ulrik Ringborg, Julio E. Celis, Manuel Heitor, Neil K. Aaronson, Nancy Abou‐Zeid, Hans‐Olov Adami, Kathi Apostolidis, Michael Baumann, Alberto Bardelli, René Bernards, Yvonne Brandberg, Carlos Caldas, Fabien Calvo, Caroline Dive, Angelika Eggert, Alexander Eggermont, Carolina Espina, Frederik Falkenburg, Jérôme Foucaud, Douglas Hanahan, Ulrike Helbig, Bengt Jönsson, Mette Kalager, Sakari Karjalainen, Miklós Kásler, Pamela Kearns, Klas Kärre, Denis Lacombe, Francesco deLorenzo, Françoise Meunier, Gerd Nettekoven, Simon Oberst, Péter Nagy, Thierry Philip, Richard Price, Joachim Schüz, Eric Solary, Peter Strang, Josep Tabernero, and Emile Voest
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cancer mission ,cancer research/care/prevention continuum ,comprehensive cancer centres ,European healthcare systems ,patient empowerment ,science policy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research–care–prevention continuum has the potential to achieve in 2030 a 10‐year cancer‐specific survival for 75% of patients diagnosed in European Union (EU) member states with a well‐developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high‐quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science‐driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC‐like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long‐term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans‐border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence‐based advice.
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- 2020
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12. Multidisciplinary approaches to enhance BRAF targeted therapy in melanoma (P2092)
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Pradeepa Narayana Pangigadde, Thomas Tan, Soldano Ferrone, Klas Karre, Francesco Colucci, and Ennio Carbone
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Immunology ,Immunology and Allergy - Abstract
40-50% of patients with melanoma are identified with BRAF mutations. About 80% of the BRAF mutations carry the V600E mutation. These patients are treated with BRAF inhibitors alone or in combination with other cell signaling pathway inhibitors. However, a relapse of the disease is observed within 6-8 months after the commencement of the therapy. Some studies hint that NK cell based therapy can be effective in controlling melanoma. In this study multidisciplinary approaches were tested to understand the mechanism of Vemurafenib resistance by a BRAFV600E melanoma. Vemurafenib is a BRAFV600E inhibitor. Vemurafenib resistant melanoma cell lines were raised from the sensitive cell lines by drug treatment till 80-90% of cells showed resistance. Both the resistant and sensitive cell lines were tested in a NK cell cytotoxicity assay in vitro by standard 51Cr-release assay. The Vemurafenib resistant cell lines were found to have a reduced sensitivity to NK cell killing. Though there was no significant difference in expression of NK cell activating ligands on the surface between the resistant and sensitive cell lines, there was a tendency of higher expression of MHC class I on Vemurafenib resistant cell lines. BRAF exon15 sequencing shows no difference between Vemurafenib resistant and sensitive cell types. Experiments are in progress to understand the mechanism(s) of the reduced sensitivity of the Vemurafenib resistant cell lines to NK cell killing.
- Published
- 2013
13. Constitutive activation of WASp leads to abnormal cytotoxic cells with increased granzyme B and degranulation response to target cells
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Joanna S. Kritikou, Mariana M.S. Oliveira, Julien Record, Mezida B. Saeed, Saket M. Nigam, Minghui He, Marton Keszei, Arnika K. Wagner, Hanna Brauner, Anton Sendel, Saikiran K. Sedimbi, Stamatina Rentouli, David P. Lane, Scott B. Snapper, Klas Kärre, Peter Vandenberghe, Jordan S. Orange, and Lisa S. Westerberg
- Subjects
Immunology ,Medicine - Abstract
X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich Syndrome protein (WASp). XLN patients have reduced numbers of cytotoxic cells in peripheral blood; however, their capacity to kill tumor cells remains to be determined. Here, we examined NK and T cells from 2 patients with XLN harboring the activating WASpL270P mutation. XLN patient NK and T cells had increased granzyme B content and elevated degranulation and IFN-γ production when compared with healthy control cells. Murine WASpL272P NK and T cells formed stable synapses with YAC-1 tumor cells and anti-CD3/CD28–coated beads, respectively. WASpL272P mouse T cells had normal degranulation and cytokine response whereas WASpL272P NK cells showed an enhanced response. Imaging experiments revealed that while WASpL272P CD8+ T cells had increased accumulation of actin upon TCR activation, WASpL272P NK cells had normal actin accumulation at lytic synapses triggered through NKp46 signaling but had impaired response to lymphocyte function associated antigen-1 engagement. When compared with WT mice, WASpL272P mice showed reduced growth of B16 melanoma and increased capacity to reject MHC class I–deficient cells. Together, our data suggest that cytotoxic cells with constitutively active WASp have an increased capacity to respond to and kill tumor cells.
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- 2021
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14. Plasma Proteomic Analysis in Non-Small Cell Lung Cancer Patients Treated with PD-1/PD-L1 Blockade
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Mohamed Eltahir, Johan Isaksson, Johanna Sofia Margareta Mattsson, Klas Kärre, Johan Botling, Martin Lord, Sara M. Mangsbo, and Patrick Micke
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lung cancer ,biomarkers ,liquid biopsy ,immune checkpoint inhibitors ,PD-L1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Checkpoint inhibitors have been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients demonstrate a durable clinical response. PD-L1 scoring is currently the only biomarker measure routinely used to select patients for immunotherapy, but its predictive accuracy is modest. The aim of our study was to evaluate a proteomic assay for the analysis of patient plasma in the context of immunotherapy. Pretreatment plasma samples from 43 NSCLC patients who received anti-PD-(L)1 therapy were analyzed using a proximity extension assay (PEA) to quantify 92 different immune oncology-related proteins. The plasma protein levels were associated with clinical and histopathological parameters, as well as therapy response and survival. Unsupervised hierarchical cluster analysis revealed two patient groups with distinct protein profiles associated with high and low immune protein levels, designated as “hot” and “cold”. Further supervised cluster analysis based on T-cell activation markers showed that higher levels of T-cell activation markers were associated with longer progression-free survival (PFS) (p < 0.01). The analysis of single proteins revealed that high plasma levels of CXCL9 and CXCL10 and low ADA levels were associated with better response and prolonged PFS (p < 0.05). Moreover, in an explorative response prediction model, the combination of protein markers (CXCL9, CXCL10, IL-15, CASP8, and ADA) resulted in higher accuracy in predicting response than tumor PD-L1 expression or each protein assayed individually. Our findings demonstrate a proof of concept for the use of multiplex plasma protein levels as a tool for anti-PD-(L)1 response prediction in NSCLC. Additionally, we identified protein signatures that could predict the response to anti-PD-(L)1 therapy.
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- 2021
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15. Expression of CD226 is associated to but not required for NK cell education
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Arnika K. Wagner, Nadir Kadri, Johanna Snäll, Petter Brodin, Susan Gilfillan, Marco Colonna, Günter Bernhardt, Petter Höglund, Klas Kärre, and Benedict J. Chambers
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Science - Abstract
CD226 is an activating receptor expressed in a co-varied manner with inhibitory receptors on natural killer (NK) cells, but whether CD226 is involved in NK cell education is unclear. Here the authors show that CD226 expression is plastic depending on the MHC environment and endows educated NK cells enhanced effector functions.
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- 2017
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16. Iron and Ferritin Modulate MHC Class I Expression and NK Cell Recognition
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Rosa Sottile, Giorgia Federico, Cinzia Garofalo, Rossana Tallerico, Maria Concetta Faniello, Barbara Quaresima, Costanza Maria Cristiani, Maddalena Di Sanzo, Gianni Cuda, Valeria Ventura, Arnika Kathleen Wagner, Gianluca Contrò, Nicola Perrotti, Elio Gulletta, Soldano Ferrone, Klas Kärre, Francesco Saverio Costanzo, Francesca Carlomagno, and Ennio Carbone
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MHC-I ,NK cells ,iron ,IFNγ ,STAT1 ,HLA ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The ability of pathogens to sequester iron from their host cells and proteins affects their virulence. Moreover, iron is required for various innate host defense mechanisms as well as for acquired immune responses. Therefore, intracellular iron concentration may influence the interplay between pathogens and immune system. Here, we investigated whether changes in iron concentrations and intracellular ferritin heavy chain (FTH) abundance may modulate the expression of Major Histocompatibility Complex molecules (MHC), and susceptibility to Natural Killer (NK) cell cytotoxicity. FTH downregulation, either by shRNA transfection or iron chelation, led to MHC surface reduction in primary cancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs) from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayed MHC class I cell surface overexpression. Low iron concentration, but not FTH, interfered with IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on the membrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, iron depletion and FTH downregulation increased the target susceptibility of both primary cancer cells and macrophages to NK cell recognition. In conclusion, the reduction of iron and FTH may influence the expression of MHC class I molecules leading to NK cells activation.
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- 2019
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17. Soluble and Exosome-Bound α-Galactosylceramide Mediate Preferential Proliferation of Educated NK Cells with Increased Anti-Tumor Capacity
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Arnika K. Wagner, Ulf Gehrmann, Stefanie Hiltbrunner, Valentina Carannante, Thuy T. Luu, Tanja I. Näslund, Hanna Brauner, Nadir Kadri, Klas Kärre, and Susanne Gabrielsson
- Subjects
extracellular vesicles ,exosomes ,natural killer (NK) cells ,innate anti-tumor response ,missing-self response ,antitumor immunity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Natural killer (NK) cells can kill target cells via the recognition of stress molecules and down-regulation of major histocompatibility complex class I (MHC-I). Some NK cells are educated to recognize and kill cells that have lost their MHC-I expression, e.g., tumor or virus-infected cells. A desired property of cancer immunotherapy is, therefore, to activate educated NK cells during anti-tumor responses in vivo. We here analyze NK cell responses to α-galactosylceramide (αGC), a potent activator of invariant NKT (iNKT) cells, or to exosomes loaded with αGC. In mouse strains which express different MHC-I alleles using an extended NK cell flow cytometry panel, we show that αGC induces a biased NK cell proliferation of educated NK cells. Importantly, iNKT cell-induced activation of NK cells selectively increased in vivo missing self-responses, leading to more effective rejection of tumor cells. Exosomes from antigen-presenting cells are attractive anti-cancer therapy tools as they may induce both innate and adaptive immune responses, thereby addressing the hurdle of tumor heterogeneity. Adding αGC to antigen-loaded dendritic-cell-derived exosomes also led to an increase in missing self-responses in addition to boosted T and B cell responses. This study manifests αGC as an attractive adjuvant in cancer immunotherapy, as it increases the functional capacity of educated NK cells and enhances the innate, missing self-based antitumor response.
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- 2021
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18. NK cells control breast cancer and related cancer stem cell hematological spread
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Rossana Tallerico, Laura Conti, Stefania Lanzardo, Rosa Sottile, Cinzia Garofalo, Arnika K. Wagner, Maria H. Johansson, Costanza Maria Cristiani, Klas Kärre, Ennio Carbone, and Federica Cavallo
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breast cancer ,cscs ,immunotherapy ,metastasization ,nk cells ,tumorspheres ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The growth and recurrence of a number of cancers is driven by a scarce population of cancer stem cells (CSCs), which are resistant to most current therapies. It has been shown previously that natural killer (NK) cells recognize human glioma, melanoma, colon and prostate CSCs in vitro. We herein show that human and mouse breast CSCs are also susceptible to NK cytotoxic activity in vitro. Moreover, CSC induced autologous NK cell activation and expansion in vivo, which correlate with the inhibition of CSC metastatic spread. These data suggest that NK cells control CSC metastatic spread in vivo and that their use in breast cancer therapy may well be fruitful.
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- 2017
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19. IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients
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Rossana Tallerico, Costanza M. Cristiani, Elina Staaf, Cinzia Garofalo, Rosa Sottile, Mariaelena Capone, Yago Pico de Coaña, Gabriele Madonna, Eleonora Palella, Maria Wolodarski, Valentina Carannante, Domenico Mallardo, Ester Simeone, Antonio M. Grimaldi, Sofia Johansson, Paolo Frumento, Elio Gulletta, Andrea Anichini, Francesco Colucci, Gennaro Ciliberto, Rolf Kiessling, Klas Kärre, Paolo A. Ascierto, and Ennio Carbone
- Subjects
anti-ctla-4 ,il-15 ,melanoma ,nk cells ,pd-1 ,tim-3 ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Despite the success of immune checkpoint blockade in melanoma, the majority of patients do not respond. We hypothesized that the T and NK cell subset frequencies and expression levels of their receptors may predict responses and clinical outcome of anti-CTLA-4 treatment. We thus characterized the NK and T cell phenotype, as well as serum levels of several cytokines in 67 melanoma patients recruited in Italy and Sweden, using samples drawn prior to and during treatment. Survival correlated with low expression of the inhibitory receptor TIM-3 on circulating T and NK cells prior to and during treatment and with the increased frequency of mature circulating NK cells (defined as CD3−CD56dim CD16+) during treatment. Survival also correlated with low levels of IL-15 in the serum. Functional experiments in vitro demonstrated that sustained exposure to IL-15 enhanced the expression of PD-1 and TIM-3 on both T and NK cells, indicating a causative link between high IL-15 levels and enhanced expression of TIM-3 on these cells. Receptor blockade of TIM-3 improved NK cell-mediated elimination of melanoma metastasis cell lines in vitro. These observations may lead to the development of novel biomarkers to predict patient response to checkpoint blockade treatment. They also suggest that induction of additional checkpoints is a possibility that needs to be considered when treating melanoma patients with IL-15.
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- 2017
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20. Intra- and interspecies reactivity of human and mouse natural killer (NK) cells
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Mona Hansson, Klas Karre Tibor Bakacs, Rolf Kiessling, and George Klein
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Cytotoxicity, Immunologic ,Male ,Isoantigens ,Leukemia ,Lymphoma ,Immunology ,Cell Line ,Antigen-Antibody Reactions ,Killer Cells, Natural ,Mice, Inbred C57BL ,Epitopes ,Mice ,Species Specificity ,Mice, Inbred CBA ,Immunology and Allergy ,Animals ,Humans ,Lymphocytes - Abstract
Natural killer (NK) cells can kill certain syngeneic, allogeneic and xenogeneic tumor targets in short-term 51Cr release assays. In the present study, intra- and interspecies NK activity was analyzed. Ten mouse and five human tissue culture lines were used. In direct cytolytic assays with mouse spleen cells or human PBL effectors, intraspecies was much stronger than interspecies reactivity, as a rule. A certain interspecies activity was obtained, stronger in mouse anti-human (M α H) than in human anti-mouse (H α M) combinations. In the H α M system, activity was associated with the same type of PBL-derived non-B-non-T cell fraction as in the intraspecies H α H system. The non-B-non-T cell nature of the M α H killer cell has been demonstrated previously. Nonlabeled tumor cells were allowed to compete with isotope-labeled targets in intra- and interspecies cytolytic NK tests. NK-sensitive tumor lines of the same species were superior to xenogeneic competitors in both M α M and H α H tests. In the M α M assay, the competing ability of the same human tumors varied, depending on the genotype of the mouse effector cells. None of the human lines tested competed effectively with strain CBA effectors but some showed a certain competition with C57BL effectors. In the H α H assay, strong competition was seen with two of the 10 xenogeneic mouse tumors tested.
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- 1978
21. Intra- and Interspecies Reactivity of Human and Mouse Natural Killer (NK) Cells
- Author
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Hansson, Mona, primary, Bakacs, Klas Karre Tibor, additional, Kiessling, Rolf, additional, and Klein, George, additional
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- 1978
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22. Mechanical stress downregulates MHC class I expression on human cancer cell membrane.
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Rosanna La Rocca, Rossana Tallerico, Almosawy Talib Hassan, Gobind Das, Tadepally Lakshmikanth, Marco Matteucci, Carlo Liberale, Maria Mesuraca, Domenica Scumaci, Francesco Gentile, Gheorghe Cojoc, Gerardo Perozziello, Antonio Ammendolia, Adriana Gallo, Klas Kärre, Giovanni Cuda, Patrizio Candeloro, Enzo Di Fabrizio, and Ennio Carbone
- Subjects
Medicine ,Science - Abstract
In our body, cells are continuously exposed to physical forces that can regulate different cell functions such as cell proliferation, differentiation and death. In this work, we employed two different strategies to mechanically stress cancer cells. The cancer and healthy cell populations were treated either with mechanical stress delivered by a micropump (fabricated by deep X-ray nanolithography) or by ultrasound wave stimuli. A specific down-regulation of Major Histocompatibility Complex (MHC) class I molecules expression on cancer cell membrane compared to different kinds of healthy cells (fibroblasts, macrophages, dendritic and lymphocyte cells) was observed, stimulating the cells with forces in the range of nano-newton, and pressures between 1 and 10 bar (1 bar = 100.000 Pascal), depending on the devices used. Moreover, Raman spectroscopy analysis, after mechanical treatment, in the range between 700-1800 cm(-1), indicated a relative concentration variation of MHC class I. PCA analysis was also performed to distinguish control and stressed cells within different cell lines. These mechanical induced phenotypic changes increase the tumor immunogenicity, as revealed by the related increased susceptibility to Natural Killer (NK) cells cytotoxic recognition.
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- 2014
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23. Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.
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Petter Brodin, Tadepally Lakshmikanth, Ramit Mehr, Maria H Johansson, Adil Doganay Duru, Adnane Achour, Mali Salmon-Divon, Klas Kärre, Petter Höglund, and Sofia Johansson
- Subjects
Medicine ,Science - Abstract
A major group of murine inhibitory receptors on Natural Killer (NK) cells belong to the Ly49 receptor family and recognize MHC class I molecules. Infected or transformed target cells frequently downmodulate MHC class I molecules and can thus avoid CD8(+) T cell attack, but may at the same time develop NK cell sensitivity, due to failure to express inhibitory ligands for Ly49 receptors. The extent of MHC class I downregulation needed on normal cells to trigger NK cell effector functions is not known. In this study, we show that cells expressing MHC class I to levels well below half of the host level are tolerated in an in vivo assay in mice. Hemizygous expression (expression from only one allele) of MHC class I was sufficient to induce Ly49 receptor downmodulation on NK cells to a similar degree as homozygous expression, despite a strongly reduced cell surface level of MHC class I. Co-expression of weaker MHC class I ligands in the host did not have any further effect on the degree of Ly49 downmodulation. Furthermore, a single MHC class I allele could downmodulate up to three Ly49 receptors on individual NK cells. Only when NK cells simultaneously expressed several Ly49 receptors and hemizygous MHC class I levels, a putative threshold for Ly49 downmodulation was reached. Collectively, our findings suggest that in interactions between NK cells and normal untransformed cells, MHC class I molecules are in most cases expressed in excess compared to what is functionally needed to ensure self tolerance and to induce maximal Ly49 downmodulation. We speculate that the reason for this is to maintain a safety margin for otherwise normal, autologous cells over a range of MHC class I expression levels, in order to ensure robustness in NK cell tolerance.
- Published
- 2010
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24. Probing natural killer cell education by Ly49 receptor expression analysis and computational modelling in single MHC class I mice.
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Sofia Johansson, Mali Salmon-Divon, Maria H Johansson, Yishai Pickman, Petter Brodin, Klas Kärre, Ramit Mehr, and Petter Höglund
- Subjects
Medicine ,Science - Abstract
Murine natural killer (NK) cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for "missing self" recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an "educating impact" on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors.
- Published
- 2009
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