36 results on '"Ramos, Rodrigo Nalio"'
Search Results
2. Author Correction: CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas
- Author
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Niborski, Leticia Laura, Gueguen, Paul, Ye, Mengliang, Thiolat, Allan, Ramos, Rodrigo Nalio, Caudana, Pamela, Denizeau, Jordan, Colombeau, Ludovic, Rodriguez, Raphaël, Goudot, Christel, Luccarini, Jean-Michel, Soudé, Anne, Bournique, Bruno, Broqua, Pierre, Pace, Luigia, Baulande, Sylvain, Sedlik, Christine, Quivy, Jean-Pierre, Almouzni, Geneviève, Cohen, José L., Zueva, Elina, Waterfall, Joshua J., Amigorena, Sebastian, and Piaggio, Eliane
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- 2023
- Full Text
- View/download PDF
3. A systematic review of clinical trials for gene therapies for β-hemoglobinopathy around the world
- Author
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Rós, Felipe Augusto, Couto, Samuel Campanelli Freitas, Milhomens, Jonathan, Ovider, Ian, Maio, Karina Tozatto, Jennifer, Viviane, Ramos, Rodrigo Nalio, Picanço-Castro, Virginia, Kashima, Simone, Calado, Rodrigo T., Barros, Luciana Rodrigues Carvalho, and Rocha, Vanderson
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- 2023
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- View/download PDF
4. Cross-sectional analysis of students and school workers reveals a high number of asymptomatic SARS-CoV-2 infections during school reopening in Brazilian cities
- Author
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Borges, Lysandro P., Guimarães, Adriana G., Fonseca, Dennyson Leandro M., Freire, Paula P., Barreto, Íkaro D.C., Souza, Daniela R.V., Gurgel, Ricardo Q., Lopes, Aline S.A., Melquiades de Rezende Neto, José, dos Santos, Kezia A., Matos, Igor L.S., da Invenção, Grazielly B., Oliveira, Brenda M., Santos, Aryanne A., Soares, Daniele Almeida, de Jesus, Pamela C., dos Santos, Cliomar A., Goes, Marco A.O., Plaça, Desirée Rodrigues, Filgueiras, Igor Salerno, Marques, Alexandre H.C., Baiocchi, Gabriela Crispim, Cabral-Miranda, William, Cabral de Miranda, Gustavo, Saraiva Camara, Niels Olsen, Garcia Calich, Vera Lúcia, Ramos, Rodrigo Nalio, Nakaya, Helder I., Rocha, Vanderson, Giil, Lasse M., Ochs, Hans D., Schimke, Lena F., de Souza, Mércia S.F., Cuevas, Luis E., Martins, Aline F., and Cabral-Marques, Otavio
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- 2022
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- View/download PDF
5. CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas
- Author
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Niborski, Leticia Laura, Gueguen, Paul, Ye, Mengliang, Thiolat, Allan, Ramos, Rodrigo Nalio, Caudana, Pamela, Denizeau, Jordan, Colombeau, Ludovic, Rodriguez, Raphaël, Goudot, Christel, Luccarini, Jean-Michel, Soudé, Anne, Bournique, Bruno, Broqua, Pierre, Pace, Luigia, Baulande, Sylvain, Sedlik, Christine, Quivy, Jean-Pierre, Almouzni, Geneviève, Cohen, José L., Zueva, Elina, Waterfall, Joshua J., Amigorena, Sebastian, and Piaggio, Eliane
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- 2022
- Full Text
- View/download PDF
6. Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. VIII: CAR-T cells: preclinical development - Safety and efficacy evaluation
- Author
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Picanço-Castro, Virginia, Bonamino, Martín Hernan, Ramos, Rodrigo Nalio, Guerino-Cunha, Renato L., Oliveira, Theo Gremen M., and Rego, Eduardo M.
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- 2021
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- View/download PDF
7. Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. VII. Present and future of technologies for production of CAR cell therapies
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Ramos, Rodrigo Nalio, Picanço-Castro, Virginia, Oliveira, Theo Gremen M., Mendrone, Alfredo, Junior, De Santis, Gil Cunha, Bonamino, Martin Hernan, and Rocha, Vanderson
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- 2021
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8. Transcriptional and Functional Analysis of CD1c+ Human Dendritic Cells Identifies a CD163+ Subset Priming CD8+CD103+ T Cells
- Author
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Bourdely, Pierre, Anselmi, Giorgio, Vaivode, Kristine, Ramos, Rodrigo Nalio, Missolo-Koussou, Yoann, Hidalgo, Sofia, Tosselo, Jimena, Nuñez, Nicolas, Richer, Wilfrid, Vincent-Salomon, Anne, Saxena, Alka, Wood, Kristie, Lladser, Alvaro, Piaggio, Eliane, Helft, Julie, and Guermonprez, Pierre
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- 2020
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9. Daro-PET: A phase 2 trial of darolutamide as a prostate-specific membrane antigen (PSMA) expression enhancer in patients with localized prostate cancer.
- Author
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Mota, Jose Mauricio, Mosci, Camila, Vasconcellos, Jéssica, Hemerly, Thiago Souto, Silva Neto, Deusdedit Cortêz Vieira, Brandao, Luis Felipe, Srougi, Victor, Ramos, Rodrigo Nalio, and Cunha, Isabela Werneck
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- 2024
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- View/download PDF
10. Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients
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Núñez, Nicolas Gonzalo, Tosello Boari, Jimena, Ramos, Rodrigo Nalio, Richer, Wilfrid, Cagnard, Nicolas, Anderfuhren, Cyrill Dimitri, Niborski, Leticia Laura, Bigot, Jeremy, Meseure, Didier, De La Rochere, Philippe, Milder, Maud, Viel, Sophie, Loirat, Delphine, Pérol, Louis, Vincent-Salomon, Anne, Sastre-Garau, Xavier, Burkhard, Becher, Sedlik, Christine, Lantz, Olivier, Amigorena, Sebastian, and Piaggio, Eliane
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- 2020
- Full Text
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11. Corrigendum to “Cross-sectional analysis of students and school workers reveals a high number of asymptomatic SARS-CoV-2 infections during school reopening in Brazilian cities” [Heliyon 8 (11) (November 2022) Article e11368]
- Author
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Borges, Lysandro P., Guimarães, Adriana G., Fonseca, Dennyson Leandro M., Freire, Paula P., Barreto, Íkaro D.C., Souza, Daniela R.V., Gurgel, Ricardo Q., Lopes, Aline S.A., Melquiades de Rezende Neto, José, dos Santos, Kezia A., Matos, Igor L.S., da Invenção, Grazielly B., Oliveira, Brenda M., Santos, Aryanne A., Soares, Daniele Almeida, de Jesus, Pamela C., dos Santos, Cliomar A., Goes, Marco A.O., Plaça, Desirée Rodrigues, Filgueiras, Igor Salerno, Marques, Alexandre H.C., Baiocchi, Gabriela Crispim, CabralMiranda, William, Cabral de Miranda, Gustavo, Saraiva Camara, Niels Olsen, Garcia Calich, Vera Lúcia, Ramos, Rodrigo Nalio, Nakaya, Helder I., Rocha, Vanderson, Giil, Lasse M., Ochs, Hans D., Schimke, Lena F., de Souza, Mércia S.F., Cuevas, Luis E., Martins, Aline F., and Cabral-Marques, Otavio
- Published
- 2023
- Full Text
- View/download PDF
12. Integrative systems immunology uncovers molecular networks of the cell cycle that stratify COVID‐19 severity.
- Author
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Prado, Caroline Aliane de Souza, Fonseca, Dennyson Leandro M., Singh, Youvika, Filgueiras, Igor Salerno, Baiocchi, Gabriela Crispim, Plaça, Desirée Rodrigues, Marques, Alexandre H. C., Dantas‐Komatsu, Raquel Costa Silva, Usuda, Júlia N., Freire, Paula Paccielli, Salgado, Ranieri Coelho, Napoleao, Sarah Maria da Silva, Ramos, Rodrigo Nalio, Rocha, Vanderson, Zhou, Guangyan, Catar, Rusan, Moll, Guido, Camara, Niels Olsen Saraiva, de Miranda, Gustavo Cabral, and Calich, Vera Lúcia Garcia
- Subjects
SARS-CoV-2 ,CELL cycle ,COVID-19 ,KILLER cells ,CYCLIN-dependent kinases ,CELL cycle proteins - Abstract
Several perturbations in the number of peripheral blood leukocytes, such as neutrophilia and lymphopenia associated with Coronavirus disease 2019 (COVID‐19) severity, point to systemic molecular cell cycle alterations during severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection. However, the landscape of cell cycle alterations in COVID‐19 remains primarily unexplored. Here, we performed an integrative systems immunology analysis of publicly available proteome and transcriptome data to characterize global changes in the cell cycle signature of COVID‐19 patients. We found significantly enriched cell cycle‐associated gene co‐expression modules and an interconnected network of cell cycle‐associated differentially expressed proteins (DEPs) and genes (DEGs) by integrating the molecular data of 1469 individuals (981 SARS‐CoV‐2 infected patients and 488 controls [either healthy controls or individuals with other respiratory illnesses]). Among these DEPs and DEGs are several cyclins, cell division cycles, cyclin‐dependent kinases, and mini‐chromosome maintenance proteins. COVID‐19 patients partially shared the expression pattern of some cell cycle‐associated genes with other respiratory illnesses but exhibited some specific differential features. Notably, the cell cycle signature predominated in the patients' blood leukocytes (B, T, and natural killer cells) and was associated with COVID‐19 severity and disease trajectories. These results provide a unique global understanding of distinct alterations in cell cycle‐associated molecules in COVID‐19 patients, suggesting new putative pathways for therapeutic intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
13. Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ
- Author
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Cabral-Marques, Otavio, Ramos, Rodrigo Nalio, Schimke, Lena F., Khan, Taj Ali, Amaral, Eduardo Pinheiro, Barbosa Bomfim, Caio César, Junior, Osvaldo Reis, França, Tabata Takahashi, Arslanian, Christina, Carola Correia Lima, Joanna Darck, Weber, Cristina Worm, Ferreira, Janaíra Fernandes, Tavares, Fabiola Scancetti, Sun, Jing, DʼImperio Lima, Maria Regina, Seelaender, Marília, Garcia Calich, Vera Lucia, Marzagão Barbuto, José Alexandre, Costa-Carvalho, Beatriz Tavares, Riemekasten, Gabriela, Seminario, Gisela, Bezrodnik, Liliana, Notarangelo, Luigi, Torgerson, Troy R., Ochs, Hans D., and Condino-Neto, Antonio
- Published
- 2017
- Full Text
- View/download PDF
14. Epigenetic control of CD8+ T cell responsiveness to a-PD-1 by Suv39h1: Contrôle épigénétique de la réactivité des cellules T CD8+ à l'a-PD-1 par Suv39h1
- Author
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Niborski, Leticia Laura, Gueguen, Paul, ye, MengLiang, Thiolat, Allan, Ramos, Rodrigo Nalio, Caudana, Pamela, Denizeau, Jordan, Goudot, Christel, Luccarini, Jean-Michel, Soudé, Anne, Bournique, Bruno, Broqua, Pierre, Pace, Luigia, Baulande, Sylvain, Sedlik, Christine, Quivy, Jean-Pierre, Amigorena, Sebastian, Almouzni, Geneviève, Cohen, José, Zueva, Elina, Waterfall, Joshua J., Piaggio, Eliane, Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Dynamique du noyau [Institut Curie], and Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
[SDV]Life Sciences [q-bio] - Abstract
Tumor-infiltrating CD8+ T cells progressively lose functionality and fail to reject tumors. Theunderlying mechanism and re-programing induced by checkpoint blockers are incompletelyunderstood. We show that genetic ablation or pharmacological inhibition of H3K9-methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In theabsence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival anddifferentiation of IFN-γ and GZMb-producing effector cells that express negativecheckpoints, but do not reach final exhaustion. Their transcriptional program correlates withthat of melanoma patients responding to immune-checkpoint blockade and identifies theemergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinicalresponse. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory andpluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effectorloci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combinedwith anti-PD-1, suggesting that Suv39h1 is an “epigenetic checkpoint” for tumor immunity.; Les cellules T CD8+ qui infiltrent les tumeurs perdent progressivement leur fonctionnalité et ne parviennent pas à rejeter les tumeurs. Le sitele mécanisme sous-jacent et la reprogrammation induite par les bloqueurs de points de contrôle sont incompletscompris. Nous montrons que l'ablation génétique ou l'inhibition pharmacologique du H3K9-méthyleLa transférase Suv39h1 retarde la croissance de la tumeur et potentialise le rejet de la tumeur par l'anti-PD-1. Dans lel'absence de Suv39h1, l'anti-PD-1 induit des voies d'activation alternatives permettant la survie etla différenciation des cellules effectrices productrices d'IFN-γ et de GZMb qui expriment desmais n'atteignent pas l'épuisement final. Leur programme de transcription est en corrélation aveccelle des patients atteints de mélanome répondant au blocage des points de contrôle immunitaire et identifie lesl'émergence de lymphocytes infiltrant les tumeurs à effecteur cytolytique comme biomarqueur desréponse. L'anti-PD-1 favorise l'ouverture de la chromatine dans les loci liés à l'activation des cellules T, à la mémoire etpluripotence, mais en l'absence de Suv39h1, les cellules acquièrent l'accessibilité dans l'effecteur cytolytiqueloci. Globalement, l'inhibition du Suv39h1 renforce les réponses immunitaires anti-tumorales, seules ou combinéesavec l'anti-PD-1, ce qui suggère que le Suv39h1 est un "point de contrôle épigénétique" pour l'immunité aux tumeurs.
- Published
- 2020
15. Contrôle épigénétique de la réactivité des cellules T CD8+ à l'a-PD-1 par Suv39h1
- Author
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Niborski, Leticia Laura, Gueguen, Paul, ye, MengLiang, Thiolat, Allan, Ramos, Rodrigo Nalio, Caudana, Pamela, Denizeau, Jordan, Goudot, Christel, Luccarini, Jean-Michel, Soudé, Anne, Bournique, Bruno, Broqua, Pierre, Pace, Luigia, Baulande, Sylvain, Sedlik, Christine, Quivy, Jean-Pierre, Amigorena, Sebastian, Almouzni, Geneviève, Cohen, José, Zueva, Elina, Waterfall, Joshua J., Piaggio, Eliane, Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Dynamique du noyau [Institut Curie], and Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
[SDV]Life Sciences [q-bio] - Abstract
Tumor-infiltrating CD8+ T cells progressively lose functionality and fail to reject tumors. Theunderlying mechanism and re-programing induced by checkpoint blockers are incompletelyunderstood. We show that genetic ablation or pharmacological inhibition of H3K9-methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In theabsence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival anddifferentiation of IFN-γ and GZMb-producing effector cells that express negativecheckpoints, but do not reach final exhaustion. Their transcriptional program correlates withthat of melanoma patients responding to immune-checkpoint blockade and identifies theemergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinicalresponse. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory andpluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effectorloci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combinedwith anti-PD-1, suggesting that Suv39h1 is an “epigenetic checkpoint” for tumor immunity.; Les cellules T CD8+ qui infiltrent les tumeurs perdent progressivement leur fonctionnalité et ne parviennent pas à rejeter les tumeurs. Le sitele mécanisme sous-jacent et la reprogrammation induite par les bloqueurs de points de contrôle sont incompletscompris. Nous montrons que l'ablation génétique ou l'inhibition pharmacologique du H3K9-méthyleLa transférase Suv39h1 retarde la croissance de la tumeur et potentialise le rejet de la tumeur par l'anti-PD-1. Dans lel'absence de Suv39h1, l'anti-PD-1 induit des voies d'activation alternatives permettant la survie etla différenciation des cellules effectrices productrices d'IFN-γ et de GZMb qui expriment desmais n'atteignent pas l'épuisement final. Leur programme de transcription est en corrélation aveccelle des patients atteints de mélanome répondant au blocage des points de contrôle immunitaire et identifie lesl'émergence de lymphocytes infiltrant les tumeurs à effecteur cytolytique comme biomarqueur desréponse. L'anti-PD-1 favorise l'ouverture de la chromatine dans les loci liés à l'activation des cellules T, à la mémoire etpluripotence, mais en l'absence de Suv39h1, les cellules acquièrent l'accessibilité dans l'effecteur cytolytiqueloci. Globalement, l'inhibition du Suv39h1 renforce les réponses immunitaires anti-tumorales, seules ou combinéesavec l'anti-PD-1, ce qui suggère que le Suv39h1 est un "point de contrôle épigénétique" pour l'immunité aux tumeurs.
- Published
- 2020
16. PD-1 blockage delays murine squamous cell carcinoma development
- Author
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Belai, Eduardo Bertoli, de Oliveira, Carine Ervolino, Gasparoto, Thaís Helena, Ramos, Rodrigo Nalio, Torres, Sergio Aparecido, Garlet, Gustavo Pompermaier, Cavassani, Karen Angélica, Silva, João Santana, and Campanelli, Ana Paula
- Published
- 2014
- Full Text
- View/download PDF
17. Systematic Review of Available CAR-T Cell Trials around the World.
- Author
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Barros, Luciana Rodrigues Carvalho, Couto, Samuel Campanelli Freitas, da Silva Santurio, Daniela, Paixão, Emanuelle Arantes, Cardoso, Fernanda, da Silva, Viviane Jennifer, Klinger, Paulo, Ribeiro, Paula do Amaral Costa, Rós, Felipe Augusto, Oliveira, Théo Gremen Mimary, Rego, Eduardo Magalhães, Ramos, Rodrigo Nalio, and Rocha, Vanderson
- Subjects
CLINICAL trials ,IMMUNE checkpoint inhibitors ,CELLULAR therapy ,SYSTEMATIC reviews ,CELL receptors ,HEMATOLOGIC malignancies ,T cells ,PHENOTYPES - Abstract
Simple Summary: CAR-T cells are genetically modified T cells that are reprogrammed to specifically eliminate cancer cells. Due to its clinical success to treat certain hematological malignancies, novel approaches to improve CAR-T cell-based therapies are being explored. This systematic review gives a worldwide overview of clinical trials evaluating new CAR-T cell therapies against different types of cancers, detailing the latest trends in CAR-T cell development. In this systematic review, we foresee what could be the approved scenario in the next few years for CAR-T cell therapies directed against hematological and solid tumor malignancies. China and the USA are the leading regions in numbers of clinical studies involving CAR-T. Hematological antigens CD19 and BCMA are the most targeted, followed by mesothelin, GPC3, CEA, MUC1, HER2, and EGFR for solid tumors. Most CAR constructs are second-generation, although third and fourth generations are being largely explored. Moreover, the benefit of combining CAR-T treatment with immune checkpoint inhibitors and other drugs is also being assessed. Data regarding product formulation and administration, such as cell phenotype, transfection technique, and cell dosage, are scarce and could not be retrieved. Better tracking of trials' status and results on the ClinicalTrials.gov database should aid in a more concise and general view of the ongoing clinical trials involving CAR-T cell therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
18. Pseudocowpox virus, a novel vector to enhance the therapeutic efficacy of antitumor vaccination.
- Author
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Ramos, Rodrigo Nalio, Tosch, Caroline, Kotsias, Fiorella, Claudepierre, Marie‐Christine, Schmitt, Doris, Remy‐Ziller, Christelle, Hoffmann, Chantal, Ricordel, Marine, Nourtier, Virginie, Farine, Isabelle, Laruelle, Laurence, Hortelano, Julie, Spring‐Giusti, Clementine, Sedlik, Christine, Le Tourneau, Christophe, Hoffmann, Caroline, Silvestre, Nathalie, Erbs, Philippe, Bendjama, Kaidre, and Thioudellet, Christine
- Abstract
Objective: Antitumor viral vaccines, and more particularly poxviral vaccines, represent an active field for clinical development and translational research. To improve the efficacy and treatment outcome, new viral vectors are sought, with emphasis on their abilities to stimulate innate immunity, to display tumor antigens and to induce a specific T‐cell response. Methods: We screened for a new poxviral backbone with improved innate and adaptive immune stimulation using IFN‐α secretion levels in infected PBMC cultures as selection criteria. Assessment of virus effectiveness was made in vitro and in vivo. Results: The bovine pseudocowpox virus (PCPV) stood out among several poxviruses for its ability to induce significant secretion of IFN‐α. PCPV produced efficient activation of human monocytes and dendritic cells, degranulation of NK cells and reversed MDSC‐induced T‐cell suppression, without being offensive to activated T cells. A PCPV‐based vaccine, encoding the HPV16 E7 protein (PCPV‐E7), stimulated strong antigen‐specific T‐cell responses in TC1 tumor‐bearing mice. Complete regression of tumors was obtained in a CD8+ T‐cell‐dependent manner after intratumoral injection of PCPV‐E7, followed by intravenous injection of the cancer vaccine MVA‐E7. PCPV also proved active when injected repeatedly intratumorally in MC38 tumor‐bearing mice, generating tumor‐specific T‐cell responses without encoding a specific MC38 antigen. From a translational perspective, we demonstrated that PCPV‐E7 effectively stimulated IFN‐γ production by T cells from tumor‐draining lymph nodes of HPV+‐infected cancer patients. Conclusion: We propose PCPV as a viral vector suitable for vaccination in the field of personalised cancer vaccines, in particular for heterologous prime‐boost regimens. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
19. Epigenetic control of CD8+ T cell responsiveness to a-PD-1 by Suv39h1
- Author
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Niborski, Leticia Laura, Gueguen, Paul, Ye, Mengliang, Thiolat, Allan, Ramos, Rodrigo Nalio, Caudana, Pamela, Denizeau, Jordan, Goudot, Christel, Luccarini, Jean-Michel, Soudé, Anne, Bournique, Bruno, Broqua, Pierre, Pace, Luigia, Baulande, Sylvain, Sedlik, Christine, Quivy, Jean-Pierre, Amigorena, Sebastian, Almouzni, Geneviève, Cohen, José, Zueva, Elina, Waterfall, Joshua J., Piaggio, Eliane, and ALMOUZNI, Geneviève
- Subjects
[SDV] Life Sciences [q-bio] - Abstract
Tumor-infiltrating CD8+ T cells progressively lose functionality and fail to reject tumors. Theunderlying mechanism and re-programing induced by checkpoint blockers are incompletelyunderstood. We show that genetic ablation or pharmacological inhibition of H3K9-methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In theabsence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival anddifferentiation of IFN-γ and GZMb-producing effector cells that express negativecheckpoints, but do not reach final exhaustion. Their transcriptional program correlates withthat of melanoma patients responding to immune-checkpoint blockade and identifies theemergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinicalresponse. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory andpluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effectorloci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combinedwith anti-PD-1, suggesting that Suv39h1 is an “epigenetic checkpoint” for tumor immunity., Les cellules T CD8+ qui infiltrent les tumeurs perdent progressivement leur fonctionnalité et ne parviennent pas à rejeter les tumeurs. Le sitele mécanisme sous-jacent et la reprogrammation induite par les bloqueurs de points de contrôle sont incompletscompris. Nous montrons que l'ablation génétique ou l'inhibition pharmacologique du H3K9-méthyleLa transférase Suv39h1 retarde la croissance de la tumeur et potentialise le rejet de la tumeur par l'anti-PD-1. Dans lel'absence de Suv39h1, l'anti-PD-1 induit des voies d'activation alternatives permettant la survie etla différenciation des cellules effectrices productrices d'IFN-γ et de GZMb qui expriment desmais n'atteignent pas l'épuisement final. Leur programme de transcription est en corrélation aveccelle des patients atteints de mélanome répondant au blocage des points de contrôle immunitaire et identifie lesl'émergence de lymphocytes infiltrant les tumeurs à effecteur cytolytique comme biomarqueur desréponse. L'anti-PD-1 favorise l'ouverture de la chromatine dans les loci liés à l'activation des cellules T, à la mémoire etpluripotence, mais en l'absence de Suv39h1, les cellules acquièrent l'accessibilité dans l'effecteur cytolytiqueloci. Globalement, l'inhibition du Suv39h1 renforce les réponses immunitaires anti-tumorales, seules ou combinéesavec l'anti-PD-1, ce qui suggère que le Suv39h1 est un "point de contrôle épigénétique" pour l'immunité aux tumeurs.
- Published
- 2020
20. Dendritic Cells from X-Linked Hyper IgM Patients Present Impaired Responses to Candida Albicans and Paracoccidioides Brasiliensis That Can Be Reversed By Exogenous Soluble Cd40l
- Author
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Marques, Otavio Cabral, Arslanian, Christina, Ramos, Rodrigo Nalio, Marques, Mariana Morato, Schimke, Lena Friederike, Soeiro, Paulo Vitor, Jancar, Sonia, Ferreira, Janaira Fernandes, Weber, Cristina Worm, Kuntze, Gisele, Rosario, Nelson Augusto, Carvalho, Beatriz Costa, Bergami-Santos, Patricia Cruz, Hackett, Mary, Ochs, Hans, Torgerson, Troy, Barbuto, José Alexandre, and Neto, Antônio Condino
- Published
- 2012
21. CD25+ T cell depletion impairs murine squamous cell carcinoma development via modulation of antitumor immune responses
- Author
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Ramos, Rodrigo Nalio, Oliveira, Carine Ervolino, Gasparoto, Thais Helena, Malaspina, Tatiana Salles de Souza, Belai, Eduardo Bertoli, Cavassani, Karen Angélica, Garlet, Gustavo Pompermaier, Silva, João Santana da, and Campanelli, Ana Paula
- Published
- 2012
- Full Text
- View/download PDF
22. Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis
- Author
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Marques, Otavio Cabral, Arslanian, Christina, Ramos, Rodrigo Nalio, Morato, Mariana, Schimke, LenaFriederike, Pereira, Paulo Vitor Soeiro, Jancar, Sonia, Ferreira, Janaíra Fernandes, Weber, Cristina Worm, Kuntze, Gisele, Rosario-Filho, Nelson Augusto, Carvalho, Beatriz Tavares Costa, Bergami-Santos, Patricia Cruz, Hackett, Mary J., Ochs, Hans D., Torgerson, Troy R., Barbuto, Jose Alexandre Marzagão, and Condino-Neto, Antonio
- Published
- 2012
- Full Text
- View/download PDF
23. Inflammatory events during murine squamous cell carcinoma development
- Author
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Gasparoto Thais Helena, de Oliveira Carine Ervolino, de Freitas Luisa Thomazini, Pinheiro Claudia Ramos, Ramos Rodrigo Nalio, da Silva André Luis, Garlet Gustavo Pompermaier, da Silva João Santana, and Campanelli Ana Paula
- Subjects
Elastase ,Nitric oxide ,Myeloperoxidase ,Inflammatory cells ,Cytokines ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Background Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. In SCC, tumour development is accompanied by an immune response that leads to massive tumour infiltration by inflammatory cells, and consequently, local and systemic production of cytokines, chemokines and other mediators. Studies in both humans and animal models indicate that imbalances in these inflammatory mediators are associated with cancer development. Methods We used a multistage model of SCC to examine the involvement of elastase (ELA), myeloperoxidase (MPO), nitric oxide (NO), cytokines (IL-6, IL-10, IL-13, IL-17, TGF-β and TNF-α), and neutrophils and macrophages in tumour development. ELA and MPO activity and NO, IL-10, IL −17, TNF-α and TGF-β levels were increased in the precancerous microenvironment. Results ELA and MPO activity and NO, IL-10, IL −17, TNF-α and TGF-β levels were increased in the precancerous microenvironment. Significantly higher levels of IL-6 and lower levels of IL-10 were detected at 4 weeks following 7,12-Dimethylbenz(a)anthracene (DMBA) treatment. Similar levels of IL-13 were detected in the precancerous microenvironment compared with control tissue. We identified significant increases in the number of GR-1+ neutrophils and F4/80+/GR-1- infiltrating cells in tissues at 4 and 8 weeks following treatment and a higher percentage of tumour-associated macrophages (TAM) expressing both GR-1 and F4/80, an activated phenotype, at 16 weeks. We found a significant correlation between levels of IL-10, IL-17, ELA, and activated TAMs and the lesions. Additionally, neutrophil infiltrate was positively correlated with MPO and NO levels in the lesions. Conclusion Our results indicate an imbalance of inflammatory mediators in precancerous SCC caused by neutrophils and macrophages and culminating in pro-tumour local tissue alterations.
- Published
- 2012
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24. CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes.
- Author
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Ramos, Rodrigo Nalio, Rodriguez, Céline, Hubert, Margaux, Ardin, Maude, Treilleux, Isabelle, Ries, Carola H, Lavergne, Emilie, Chabaud, Sylvie, Colombe, Amélie, Trédan, Olivier, Guedes, Henrique Gomes, Laginha, Fábio, Richer, Wilfrid, Piaggio, Eliane, Barbuto, José Alexandre M, Caux, Christophe, Ménétrier‐Caux, Christine, and Bendriss‐Vermare, Nathalie
- Subjects
- *
CANCER patients , *BREAST cancer , *PROGRAMMED death-ligand 1 , *BLOOD donors , *FLOW cytometry - Abstract
Objectives: The accumulation of tumor‐associated macrophages (TAMs) is correlated with poor clinical outcome, but the mechanisms governing their differentiation from circulating monocytes remain unclear in humans. Methods: Using multicolor flow cytometry, we evaluated TAMs phenotype in 93 breast cancer (BC) patients. Furthermore, monocytes from healthy donors were cultured in the presence of supernatants from dilacerated primary tumors to investigate their differentiation into macrophages (MΦ) in vitro. Additionally, we used transcriptomic analysis to evaluate BC patients' blood monocytes profiles. Results: We observed that high intra‐tumor CD163‐expressing TAM density is predictive of reduced survival in BC patients. In vitro, M‐CSF, TGF‐β and VEGF from primary tumor supernatants skewed the differentiation of healthy donor blood monocytes towards CD163highCD86lowIL‐10high M2‐like MΦ that strongly suppressed CD4+ T‐cell expansion via PD‐L1 and IL‐10. In addition, blood monocytes from about 40% of BC patients displayed an altered response to in vitro stimulation, being refractory to type‐1 MΦ (M1‐MΦ) differentiation and secreting higher amounts of immunosuppressive, metastatic‐related and angiogenic cytokines. Aside from showing that monocyte transcriptome is significantly altered by the presence of BC, we also demonstrated an overall metabolic de‐activation in refractory monocytes of BC patients. In contrast, monocytes from sensitive BC patients undergoing normal M1‐MΦ differentiation showed up‐regulation of IFN‐response genes and had no signs of metabolic alteration. Conclusion: Altogether, our results suggest that systemic factors skew BC patient blood monocytes towards a pro‐metastatic profile, resulting in the accumulation of further polarised CD163high TAMs resembling type‐2 MΦ (M2‐MΦ) in the local BC microenvironment. These data indicate that monitoring circulating monocytes in BC patients may provide an indication of early systemic alterations induced by cancer and, thus, be instrumental in the development of improved personalised immunotherapeutic interventions. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
25. Flow Cytometry Contributions for the Diagnosis and Immunopathological Characterization of Primary Immunodeficiency Diseases With Immune Dysregulation.
- Author
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Cabral-Marques, Otavio, Schimke, Lena F., de Oliveira, Edgar Borges, El Khawanky, Nadia, Ramos, Rodrigo Nalio, Al-Ramadi, Basel K., Segundo, Gesmar Rodrigues Silva, Ochs, Hans D., and Condino-Neto, Antonio
- Subjects
FLOW cytometry ,IMMUNOLOGIC diseases ,PRIMARY immunodeficiency diseases ,IMMUNODEFICIENCY ,GENETIC testing ,GAIN-of-function mutations - Abstract
Almost 70 years after establishing the concept of primary immunodeficiency disorders (PIDs), more than 320 monogenic inborn errors of immunity have been identified thanks to the remarkable contribution of high-throughput genetic screening in the last decade. Approximately 40 of these PIDs present with autoimmune or auto-inflammatory symptoms as the primary clinical manifestation instead of infections. These PIDs are now recognized as diseases of immune dysregulation. Loss-of function mutations in genes such as FOXP3, CD25, LRBA, IL-10, IL10RA, and IL10RB , as well as heterozygous gain-of-function mutations in JAK1 and STAT3 have been reported as causative of these disorders. Identifying these syndromes has considerably contributed to expanding our knowledge on the mechanisms of immune regulation and tolerance. Although whole exome and whole genome sequencing have been extremely useful in identifying novel causative genes underlying new phenotypes, these approaches are time-consuming and expensive. Patients with monogenic syndromes associated with autoimmunity require faster diagnostic tools to delineate therapeutic strategies and avoid organ damage. Since these PIDs present with severe life-threatening phenotypes, the need for a precise diagnosis in order to initiate appropriate patient management is necessary. More traditional approaches such as flow cytometry are therefore a valid option. Here, we review the application of flow cytometry and discuss the relevance of this powerful technique in diagnosing patients with PIDs presenting with immune dysregulation. In addition, flow cytometry represents a fast, robust, and sensitive approach that efficiently uncovers new immunopathological mechanisms underlying monogenic PIDs. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
26. What Are the Molecules Involved in Regulatory T-Cells Induction by Dendritic Cells in Cancer?
- Author
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Ramos, Rodrigo Nalio, Moraes, Cristiano Jacob de, Zelante, Bruna, and Barbuto, José Alexandre M.
- Subjects
Article Subject - Abstract
Dendritic cells (DCs) are essential for the maintenance of homeostasis in the organism, and they do that by modulating lymphocyte priming, expansion, and response patterns according to signals they receive from the environment. The induction of suppressive lymphocytes by DCs is essential to hinder the development of autoimmune diseases but can be reverted against homeostasis when in the context of neoplasia. In this setting, the induction of suppressive or regulatory T cells contributes to the establishment of a state of tolerance towards the tumor, allowing it to grow unchecked by an otherwise functional immune system. Besides affecting its local environment, tumor also has been described as potent sources of anti-inflammatory/suppressive factors, which may act systemically, generating defects in the differentiation and maturation of immune cells, far beyond the immediate vicinity of the tumor mass. Cytokines, as IL-10 and TGF-beta, as well as cell surface molecules like PD-L1 and ICOS seem to be significantly involved in the redirection of DCs towards tolerance induction, and recent data suggest that tumor cells may, indeed, modulate distinct DCs subpopulations through the involvement of these molecules. It is to be expected that the identification of such molecules should provide molecular targets for more effective immunotherapeutic approaches to cancer.
- Published
- 2013
- Full Text
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27. Mesenchymal Stem Cells Derived from Human Exfoliated Deciduous Teeth (SHEDs) Induce Immune Modulatory Profile in Monocyte-Derived Dendritic Cells.
- Author
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Silva, Fernando de Sá, Ramos, Rodrigo Nalio, Almeida, Danilo Candido de, Bassi, Enio Jose, Gonzales, Roberto Pereira, Miyagi, Sueli Patricia Harumi, Maranduba, Claudinéia Pereira, Sant'Anna, Osvaldo Augusto Brazil Esteves, Marques, Márcia Martins, Barbuto, José Alexandre Marzagão, Câmara, Niels Olsen Saraiva, and da Costa Maranduba, Carlos Magno
- Subjects
- *
MESENCHYMAL stem cells , *DECIDUOUS teeth , *IMMUNOLOGICAL adjuvants , *MONOCYTES , *DENDRITIC cells , *CELL differentiation , *T cells - Abstract
Background: Mesenchymal stem cells have prominent immune modulatory properties, which may have clinical applications; however their major source, bone marrow, is of limited availability. On the other hand, mesenchymal stem cells derived from human exfoliated deciduous teeth (SHEDs) are readily accessible, but their immune regulatory properties have not been completely investigated. This study was designed, therefore, to evaluate the SHEDs influence on DCs differentiation, maturation, ability to activate T cells and to expand CD4+Foxp3+ T cells. Methodology/Principal Findings: The experiments were based in cellular co-culture during differentiation and maturation of monocyte derived-DCs (moDCs), with, or not, presence of SHEDs. After co-culture with SHEDs, (moDCs) presented lower expression of BDCA-1 and CD11c, in comparison to DC cultivated without SHEDs. CD40, CD80, CD83 and CD86 levels were also decreased in mature DCs (mDCs) after co-cultivation with SHEDs. To assess the ability of SHEDs-exposed moDCs to modulate T cell responses, the former were separated from SHEDs, and co-cultured with peripheral blood lymphocytes. After 5 days, the proliferation of CD4+ and CD8+ T cells was evaluated and found to be lower than that induced by moDCs cultivated without SHEDs. In addition, an increase in the proportion of CD4+Foxp3+IL-10+ T cells was observed among cells stimulated by mature moDCs that were previously cultivated with SHEDs. Soluble factors released during co-cultures also showed a reduction in the pro-inflammatory cytokines (IL-2, TNF-α and IFN-γ), and an increase in the anti-inflammatory molecule IL-10. Conclusion/Significance: This study shows that SHEDs induce an immune regulatory phenotype in moDCs cells, evidenced by changes in maturation and differentiation rates, inhibition of lymphocyte stimulation and ability to expand CD4+Foxp3+ T cells. Further characterization and validation of this phenomenon could support the use of SHEDs, directly or indirectly for immune modulation in the clinical practice. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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28. Soluble Uric Acid Activates the NLRP3 Inflammasome.
- Author
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Braga, Tarcio Teodoro, Forni, Maria Fernanda, Correa-Costa, Matheus, Ramos, Rodrigo Nalio, Barbuto, Jose Alexandre, Branco, Paola, Castoldi, Angela, Hiyane, Meire Ioshie, Davanso, Mariana Rodrigues, Latz, Eicke, Franklin, Bernardo S., Kowaltowski, Alicia J., and Camara, Niels Olsen Saraiva
- Abstract
Uric acid is a damage-associated molecular pattern (DAMP), released from ischemic tissues and dying cells which, when crystalized, is able to activate the NLRP3 inflammasome. Soluble uric acid (sUA) is found in high concentrations in the serum of great apes, and even higher in some diseases, before the appearance of crystals. In the present study, we sought to investigate whether uric acid, in the soluble form, could also activate the NLRP3 inflammasome and induce the production of IL-1β. We monitored ROS, mitochondrial area and respiratory parameters from macrophages following sUA stimulus. We observed that sUA is released in a hypoxic environment and is able to induce IL-1β release. This process is followed by production of mitochondrial ROS, ASC speck formation and caspase-1 activation. Nlrp3
−/− macrophages presented a protected redox state, increased maximum and reserve oxygen consumption ratio (OCR) and higher VDAC protein levels when compared to WT and Myd88−/− cells. Using a disease model characterized by increased sUA levels, we observed a correlation between sUA, inflammasome activation and fibrosis. These findings suggest sUA activates the NLRP3 inflammasome. We propose that future therapeutic strategies for renal fibrosis should include strategies that block sUA or inhibit its recognition by phagocytes. [ABSTRACT FROM AUTHOR]- Published
- 2017
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29. Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors.
- Author
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Leruste, Amaury, Tosello, Jimena, Ramos, Rodrigo Nalio, Tauziède-Espariat, Arnault, Brohard, Solène, Han, Zhi-Yan, Beccaria, Kevin, Andrianteranagna, Mamy, Caudana, Pamela, Nikolic, Jovan, Chauvin, Céline, Niborski, Leticia Laura, Manriquez, Valeria, Richer, Wilfrid, Masliah-Planchon, Julien, Grossetête-Lalami, Sandrine, Bohec, Mylene, Lameiras, Sonia, Baulande, Sylvain, and Pouponnot, Celio
- Subjects
- *
T cell receptors , *T cells , *NUCLEOTIDE sequence , *ENDOGENOUS retroviruses , *DNA fingerprinting , *IMMUNOLOGIC memory - Abstract
Rhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1 , leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8+ T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation. • Genomically simple RTs are infiltrated by T cell and myeloid populations • Clonally expanded T cell phenotypes suggest a tumor-specific response • Checkpoint blockade induces tumor regression and immune memory in vivo • Endogenous retrovirus expression is linked to the immunogenicity of RTs Leruste et al. find that, despite their low mutation burden, rhabdoid tumors have a high rate of infiltration by T cells and myeloid cells, and the immunogenicity is linked to endogenous retrovirus expression. Immune checkpoint blockade induces tumor regression in a rhabdoid tumor mouse model. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
30. Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion.
- Author
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Nader, Guilherme Pedreira de Freitas, Agüera-Gonzalez, Sonia, Routet, Fiona, Gratia, Matthieu, Maurin, Mathieu, Cancila, Valeria, Cadart, Clotilde, Palamidessi, Andrea, Ramos, Rodrigo Nalio, San Roman, Mabel, Gentili, Matteo, Yamada, Ayako, Williart, Alice, Lodillinsky, Catalina, Lagoutte, Emilie, Villard, Catherine, Viovy, Jean-Louis, Tripodo, Claudio, Galon, Jérôme, and Scita, Giorgio
- Subjects
- *
NUCLEAR membranes , *DNA damage , *CELL nuclei , *BREAST cancer , *MUSCULAR dystrophy , *ENDOPLASMIC reticulum , *CANCER cells - Abstract
Although mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced nuclear envelope ruptures are less known. Here, we show that nuclear envelope ruptures induce DNA damage that promotes senescence in non-transformed cells and induces an invasive phenotype in human breast cancer cells. We find that the endoplasmic reticulum (ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells. [Display omitted] • Deformed nuclei and DNA damage are enriched at micro-invasive foci of breast cancer • TREX1 causes DNA damage in deformed nuclei upon nuclear envelope rupture events • TREX1 drives senescence in normal cells and an invasive phenotype in cancer cells • Nuclear envelope rupture events and DNA damage are observed in human tumors Extreme nuclear deformations in dense microenvironments lead to repeated nuclear envelope rupture followed by TREX1-dependent chronic DNA damage. This triggers a partial EMT in malignant cells which might underlie tumor progression. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
31. Editorial: Tumor microenvironment (TME) and tumor immune microenvironment (TIME): New perspectives for prognosis and therapy.
- Author
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Ramos RN, Amano MT, Paes Leme AF, Fox JW, and de Oliveira AK
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
- Full Text
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32. Myeloid Immune Cells CARrying a New Weapon Against Cancer.
- Author
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Ramos RN, Couto SCF, Oliveira TGM, Klinger P, Braga TT, Rego EM, Barbuto JAM, and Rocha V
- Abstract
Chimeric antigen receptor (CAR) engineering for T cells and natural killer cells (NK) are now under clinical evaluation for the treatment of hematologic cancers. Although encouraging clinical results have been reported for hematologic diseases, pre-clinical studies in solid tumors have failed to prove the same effectiveness. Thus, there is a growing interest of the scientific community to find other immune cell candidate to express CAR for the treatment of solid tumors and other diseases. Mononuclear phagocytes may be the most adapted group of cells with potential to overcome the dense barrier imposed by solid tumors. In addition, intrinsic features of these cells, such as migration, phagocytic capability, release of soluble factors and adaptive immunity activation, could be further explored along with gene therapy approaches. Here, we discuss the elements that constitute the tumor microenvironment, the features and advantages of these cell subtypes and the latest studies using CAR-myeloid immune cells in solid tumor models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ramos, Couto, Oliveira, Klinger, Braga, Rego, Barbuto and Rocha.)
- Published
- 2021
- Full Text
- View/download PDF
33. CD163 + tumor-associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes.
- Author
-
Ramos RN, Rodriguez C, Hubert M, Ardin M, Treilleux I, Ries CH, Lavergne E, Chabaud S, Colombe A, Trédan O, Guedes HG, Laginha F, Richer W, Piaggio E, Barbuto JAM, Caux C, Ménétrier-Caux C, and Bendriss-Vermare N
- Abstract
Objectives: The accumulation of tumor-associated macrophages (TAMs) is correlated with poor clinical outcome, but the mechanisms governing their differentiation from circulating monocytes remain unclear in humans., Methods: Using multicolor flow cytometry, we evaluated TAMs phenotype in 93 breast cancer (BC) patients. Furthermore, monocytes from healthy donors were cultured in the presence of supernatants from dilacerated primary tumors to investigate their differentiation into macrophages (MΦ) in vitro . Additionally, we used transcriptomic analysis to evaluate BC patients' blood monocytes profiles., Results: We observed that high intra-tumor CD163-expressing TAM density is predictive of reduced survival in BC patients. In vitro , M-CSF, TGF-β and VEGF from primary tumor supernatants skewed the differentiation of healthy donor blood monocytes towards CD163
high CD86low IL-10high M2-like MΦ that strongly suppressed CD4+ T-cell expansion via PD-L1 and IL-10. In addition, blood monocytes from about 40% of BC patients displayed an altered response to in vitro stimulation, being refractory to type-1 MΦ (M1-MΦ) differentiation and secreting higher amounts of immunosuppressive, metastatic-related and angiogenic cytokines. Aside from showing that monocyte transcriptome is significantly altered by the presence of BC, we also demonstrated an overall metabolic de-activation in refractory monocytes of BC patients. In contrast, monocytes from sensitive BC patients undergoing normal M1-MΦ differentiation showed up-regulation of IFN-response genes and had no signs of metabolic alteration., Conclusion: Altogether, our results suggest that systemic factors skew BC patient blood monocytes towards a pro-metastatic profile, resulting in the accumulation of further polarised CD163high TAMs resembling type-2 MΦ (M2-MΦ) in the local BC microenvironment. These data indicate that monitoring circulating monocytes in BC patients may provide an indication of early systemic alterations induced by cancer and, thus, be instrumental in the development of improved personalised immunotherapeutic interventions., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)- Published
- 2020
- Full Text
- View/download PDF
34. A Milestone Review on How Macrophages Affect Tumor Growth.
- Author
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Caux C, Ramos RN, Prendergast GC, Bendriss-Vermare N, and Ménétrier-Caux C
- Subjects
- Animals, Humans, Macrophages pathology, Neoplasms pathology
- Published
- 2016
- Full Text
- View/download PDF
35. Monocyte-derived dendritic cells from breast cancer patients are biased to induce CD4+CD25+Foxp3+ regulatory T cells.
- Author
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Ramos RN, Chin LS, Dos Santos AP, Bergami-Santos PC, Laginha F, and Barbuto JA
- Subjects
- Coculture Techniques, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Forkhead Transcription Factors immunology, Humans, Interleukin-2 Receptor alpha Subunit immunology, Monocytes immunology, Breast Neoplasms immunology, Dendritic Cells immunology, Lymphocyte Activation immunology, T-Lymphocytes, Regulatory immunology, Tumor Escape immunology
- Abstract
DCs orchestrate immune responses contributing to the pattern of response developed. In cancer, DCs may play a dysfunctional role in the induction of CD4(+)CD25(+)Foxp3(+) Tregs, contributing to immune evasion. We show here that Mo-DCs from breast cancer patients show an altered phenotype and induce preferentially Tregs, a phenomenon that occurred regardless of DC maturation stimulus (sCD40L, cytokine cocktail, TNF-α, and LPS). The Mo-DCs of patients induced low proliferation of allogeneic CD3(+)CD25(neg)Foxp3(neg) cells, which after becoming CD25(+), suppressed mitogen-stimulated T cells. Contrastingly, Mo-DCs from healthy donors induced a stronger proliferative response, a low frequency of CD4(+)CD25(+)Foxp3(+) with no suppressive activity. Furthermore, healthy Mo-DCs induced higher levels of IFN-γ, whereas the Mo-DCs of patients induced higher levels of bioactive TGF-β1 and IL-10 in cocultures with allogeneic T cells. Interestingly, TGF-β1 blocking with mAb in cocultures was not enough to completely revert the Mo-DCs of patients' bias toward Treg induction. Altogether, these findings should be considered in immunotherapeutic approaches for cancer based on Mo-DCs.
- Published
- 2012
- Full Text
- View/download PDF
36. Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis.
- Author
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Cabral-Marques O, Arslanian C, Ramos RN, Morato M, Schimke L, Soeiro Pereira PV, Jancar S, Ferreira JF, Weber CW, Kuntze G, Rosario-Filho NA, Costa Carvalho BT, Bergami-Santos PC, Hackett MJ, Ochs HD, Torgerson TR, Barbuto JA, and Condino-Neto A
- Subjects
- Adolescent, B7-1 Antigen genetics, B7-1 Antigen metabolism, B7-2 Antigen genetics, B7-2 Antigen metabolism, CD40 Ligand genetics, CD40 Ligand immunology, CD40 Ligand metabolism, Candida albicans pathogenicity, Candidiasis complications, Candidiasis genetics, Cell Differentiation drug effects, Cell Differentiation genetics, Cell Proliferation, Cells, Cultured, Child, Child, Preschool, Coculture Techniques, Cytokines metabolism, Dendritic Cells drug effects, Dendritic Cells immunology, Dendritic Cells pathology, Dendritic Cells virology, Female, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Histocompatibility Antigens Class II genetics, Histocompatibility Antigens Class II metabolism, Humans, Hyper-IgM Immunodeficiency Syndrome, Type 1 complications, Hyper-IgM Immunodeficiency Syndrome, Type 1 genetics, Lymphocyte Activation drug effects, Lymphocyte Activation genetics, Male, Mutation genetics, Paracoccidioides pathogenicity, Paracoccidioidomycosis complications, Paracoccidioidomycosis genetics, Th17 Cells immunology, Th17 Cells metabolism, Th17 Cells pathology, Candida albicans immunology, Candidiasis immunology, Dendritic Cells metabolism, Hyper-IgM Immunodeficiency Syndrome, Type 1 immunology, Paracoccidioides immunology, Paracoccidioidomycosis immunology
- Abstract
Background: Patients with X-linked hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) mutations are susceptible to fungal pathogens; however, the underlying susceptibility mechanisms remain poorly understood., Objective: To determine whether monocyte-derived dendritic cells (DCs) from patients with X-HIGM exhibit normal responses to fungal pathogens., Methods: DCs from patients and controls were evaluated for the expression of costimulatory (CD80 and CD86) and MHC class II molecules and for their ability to produce IL-12 and IL-10 in response to Candida albicans and Paracoccidioides brasiliensis. We also evaluated the ability of C albicans- and P brasiliensis-pulsed mature DCs to induce autologous T-cell proliferation, generation of T helper (T(H)) 17 cells, and production of IFN-γ, TGF-β, IL-4, IL-5, and IL-17., Results: Immature DCs from patients with X-HIGM showed reduced expression of CD80, CD86, and HLA-DR, which could be reversed by exogenous trimeric soluble CD40L. Most important, mature DCs from patients with X-HIGM differentiated by coculturing DCs with fungi secreted minimal amounts of IL-12 but substantial amounts of IL-10 compared with mature DCs from normal individuals. Coculture of mature DCs from X-HIGM patients with autologous T cells led to low IFN-γ production, whereas IL-4 and IL-5 production was increased. T-cell proliferation and IL-17 secretion were normal. Finally, in vitro incubation with soluble CD40L reversed the decreased IL-12 production and the skewed T(H)2 pattern response., Conclusion: Absence of CD40L during monocyte/DC differentiation leads to functional DC abnormalities, which may contribute to the susceptibility to fungal infections in patients with X-HIGM., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
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