29 results on '"Jilkova, Zuzana Macek"'
Search Results
2. SAT-389 HBV and HBsAg strongly reshape the phenotype, function and metabolism of DCs according to patients’ clinical stage
- Author
-
Dumolard, Lucile, primary, Théophile, Gerster, additional, Chuffart, Florent, additional, Decaens, Thomas, additional, Hilleret, Marie-Noëlle, additional, Larrat, Sylvie, additional, Saas, Philippe, additional, Jouvin-Marche, Evelyne, additional, Durantel, David, additional, Marche, Patrice N, additional, Jilkova, Zuzana Macek, additional, and Aspord, Caroline, additional
- Published
- 2024
- Full Text
- View/download PDF
3. SAT-396 Differences in the intrahepatic expression of immune checkpoint molecules on T cells and natural killer cells in chronic HBV patients
- Author
-
Dumolard, Lucile, primary, Hilleret, Marie-Noëlle, additional, Théophile, Gerster, additional, Costentin, Charlotte, additional, Decaens, Thomas, additional, Jouvin-Marche, Evelyne, additional, Marche, Patrice N, additional, and Jilkova, Zuzana Macek, additional
- Published
- 2024
- Full Text
- View/download PDF
4. NASH limits anti-tumour surveillance in immunotherapy-treated HCC
- Author
-
Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K., Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M., Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D’Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K., Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M., Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G., Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G., Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E., Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz de Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-Francois, Marron, Thomas U., Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N., Decaens, Thomas, Pinato, David J., Rad, Roland, Mertens, Joachim C., Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M., Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M., and Heikenwalder, Mathias
- Published
- 2021
- Full Text
- View/download PDF
5. Harnessing Immune Cell Metabolism to Modulate Alloresponse in Transplantation.
- Author
-
Noble, Johan, Jilkova, Zuzana Macek, Aspord, Caroline, Malvezzi, Paolo, Fribourg, Miguel, Riella, Leonardo V., and Cravedi, Paolo
- Subjects
- *
CELL metabolism , *REGULATORY T cells , *IMMUNE response , *FATTY acid oxidation , *CELL morphology - Abstract
Immune cell metabolism plays a pivotal role in shaping and modulating immune responses. The metabolic state of immune cells influences their development, activation, differentiation, and overall function, impacting both innate and adaptive immunity. While glycolysis is crucial for activation and effector function of CD8 T cells, regulatory T cells mainly use oxidative phosphorylation and fatty acid oxidation, highlighting how different metabolic programs shape immune cells. Modification of cell metabolism may provide new therapeutic approaches to prevent rejection and avoid immunosuppressive toxicities. In particular, the distinct metabolic patterns of effector and suppressive cell subsets offer promising opportunities to target metabolic pathways that influence immune responses and graft outcomes. Herein, we review the main metabolic pathways used by immune cells, the techniques available to assay immune metabolism, and evidence supporting the possibility of shifting the immune response towards a tolerogenic profile by modifying energetic metabolism. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
6. Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet
- Author
-
Iuso, Domenico, primary, Garcia-Saez, Isabel, additional, Couté, Yohann, additional, Yamaryo-Botté, Yoshiki, additional, Boeri Erba, Elisabetta, additional, Adrait, Annie, additional, Zeaiter, Nour, additional, Tokarska-Schlattner, Malgorzata, additional, Jilkova, Zuzana Macek, additional, Boussouar, Fayçal, additional, Barral, Sophie, additional, Signor, Luca, additional, Couturier, Karine, additional, Hajmirza, Azadeh, additional, Chuffart, Florent, additional, Bourova-Flin, Ekaterina, additional, Vitte, Anne-Laure, additional, Bargier, Lisa, additional, Puthier, Denis, additional, Decaens, Thomas, additional, Rousseaux, Sophie, additional, Botté, Cyrille, additional, Schlattner, Uwe, additional, Petosa, Carlo, additional, and Khochbin, Saadi, additional
- Published
- 2023
- Full Text
- View/download PDF
7. Role of Genetic and Epigenetic Modifications in the Progression of Hepatocellular Carcinoma in Chronic HCV Patients
- Author
-
Syyam, Anum, primary, Akbar, Hira Raheem, additional, Jilkova, Zuzana Macek, additional, and Afzal, Samia, additional
- Published
- 2023
- Full Text
- View/download PDF
8. Lymphocytes Degranulation in Liver in Hepatitis C Virus Carriers Is Associated With IFNL4 Polymorphisms and ALT Levels
- Author
-
Jouvin-Marche, Evelyne, Jílková, Zuzana Macek, Thelu, Marie-Ange, Marche, Helene, Fugier, Emilie, Van Campenhout, Nicolas, Hoang, Xuan Su, Marlu, Alice, Sturm, Nathalie, Callanan, Mary, Leroy, Vincent, Zarski, Jean-Pierre, and Marche, Patrice N.
- Published
- 2014
9. Immune checkpoints on T and NK cells in the context of HBV infection: Landscape, pathophysiology and therapeutic exploitation.
- Author
-
Dumolard, Lucile, Aspord, Caroline, Marche, Patrice N., and Jilkova, Zuzana Macek
- Subjects
HEPATITIS B ,KILLER cells ,IMMUNE checkpoint proteins ,T cells ,CYTOTOXIC T cells - Abstract
In hepatitis B virus (HBV) infection, the interplay between the virus and the host immune system is crucial in determining the pathogenesis of the disease. Patients who fail to mount a sufficient and sustained anti-viral immune response develop chronic hepatitis B (CHB). T cells and natural killer (NK) cells play decisive role in viral clearance, but they are defective in chronic HBV infection. The activation of immune cells is tightly controlled by a combination of activating and inhibitory receptors, called immune checkpoints (ICs), allowing the maintenance of immune homeostasis. Chronic exposure to viral antigens and the subsequent dysregulation of ICs actively contribute to the exhaustion of effector cells and viral persistence. The present review aims to summarize the function of various ICs and their expression in T lymphocytes and NK cells in the course of HBV infection as well as the use of immunotherapeutic strategies targeting ICs in chronic HBV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
10. Increased Intrahepatic Expression of Immune Checkpoint Molecules in Autoimmune Liver Disease
- Author
-
Jilkova, Zuzana Macek, Hilleret, Marie Noelle, Gerster, Theophile, Sturm, Nathalie, Mercey-Ressejac, Marion, Zarski, Jean-Pierre, Leroy, Vincent, Marche, Patrice N., Costentin, Charlotte, and Decaens, Thomas
- Subjects
Male ,autoimmune hepatitis ,QH301-705.5 ,Liver Diseases ,autoimmune liver disease ,CD8-Positive T-Lymphocytes ,Middle Aged ,Immune Checkpoint Proteins ,Models, Biological ,Article ,Autoimmune Diseases ,4-1BB ,Liver ,immune checkpoint molecules ,embryonic structures ,PD-1 ,Humans ,Female ,Lymphocytes ,Biology (General) ,Biomarkers - Abstract
Immune checkpoint molecules (ICM) are critical in maintaining immunologic homeostasis and participate in preventing or promoting autoimmune disease development. Exploring a large panel of intrahepatic inhibitory and stimulatory ICM is necessary for drawing a general picture of the immune alterations in autoimmune hepatitis (AIH). Here, we performed a multiparametric analysis of ICM, including PD-1, TIM3, LAG3, CTLA-4, OX40 and 4-1BB, and we determined their expression on intrahepatic lymphocyte subsets in untreated and in treated patients with AIH in comparison to normal liver tissue. AIH patient-derived liver tissue revealed the overexpression of ICM, mainly PD-1 and 4-1BB, as well as the strong correlation between PD-1+ CD8+ T-cell abundance and severity of AIH (alanine transaminase and aspartate transaminase levels). Our results show that the ICM play an important role in the loss of immune homeostasis in the liver, providing an attractive approach to investigate their role as targets for effective therapeutic interventions.
- Published
- 2021
11. Perinatal programming of body weight control by leptin: putative roles of AMP kinase and muscle thermogenesis
- Author
-
Pico, Catalina, Jilkova, Zuzana Macek, Kus, Vladimir, Palou, Andreu, and Kopecky, Jan
- Published
- 2011
- Full Text
- View/download PDF
12. GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions
- Author
-
Brun, Sonia, primary, Bestion, Eloïne, additional, Raymond, Eric, additional, Bassissi, Firas, additional, Jilkova, Zuzana Macek, additional, Mezouar, Soraya, additional, Rachid, Madani, additional, Novello, Marie, additional, Tracz, Jennifer, additional, Hamaï, Ahmed, additional, Lalmanach, Gilles, additional, Vanderlynden, Lise, additional, Legouffe, Raphael, additional, Stauber, Jonathan, additional, Schubert, Thomas, additional, Plach, Maximilian G., additional, Courcambeck, Jérôme, additional, Drouot, Cyrille, additional, Jacquemot, Guillaume, additional, Serdjebi, Cindy, additional, Roth, Gael, additional, Baudoin, Jean-Pierre, additional, Ansaldi, Christelle, additional, Decaens, Thomas, additional, and Halfon, Philippe, additional
- Published
- 2021
- Full Text
- View/download PDF
13. GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions
- Author
-
Brun, Sonia, Bestion, Eloïne, Raymond, Eric, Bassissi, Firas, Jilkova, Zuzana Macek, Mezouar, Soraya, Rachid, Madani, Novello, Marie, Tracz, Jennifer, Hamaï, Ahmed, Lalmanach, Gilles, Vanderlynden, Lise, Legouffe, Raphael, Stauber, Jonathan, Schubert, Thomas, Plach, Maximilian G., Courcambeck, Jérôme, Drouot, Cyrille, Jacquemot, Guillaume, Serdjebi, Cindy, Roth, Gael, Baudoin, Jean-Pierre, Ansaldi, Christelle, Decaens, Thomas, and Halfon, Philippe
- Abstract
Hepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two hepatocellular carcinoma in vivo models. We showed that due to its lysosomotropic properties, GNS561 could reach and specifically inhibited its enzyme target, PPT1 (palmitoyl-protein thioesterase 1), resulting in lysosomal unbound Zn2+ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of MTOR (mechanistic target of rapamycin kinase), lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, for which a global phase 1b clinical trial in liver cancers was just successfully achieved, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment. Abbreviations: ANXA5:annexin A5; ATCC: American type culture collection; BafA1: bafilomycin A1; BSA: bovine serum albumin; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CCND1: cyclin D1; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; CQ: chloroquine; iCCA: intrahepatic cholangiocarcinoma; DEN: diethylnitrosamine; DMEM: Dulbelcco’s modified Eagle medium; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCC: hepatocellular carcinoma; HCQ: hydroxychloroquine; HDSF: hexadecylsulfonylfluoride; IC50: mean half-maximal inhibitory concentration; LAMP: lysosomal associated membrane protein; LC3-II: phosphatidylethanolamine-conjugated form of MAP1LC3; LMP: lysosomal membrane permeabilization; MALDI: matrix assisted laser desorption ionization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation Ki-67; MTOR: mechanistic target of rapamycin kinase; MRI: magnetic resonance imaging; NH4Cl: ammonium chloride; NtBuHA: N-tert-butylhydroxylamine; PARP: poly(ADP-ribose) polymerase; PBS: phosphate-buffered saline; PPT1: palmitoyl-protein thioesterase 1; SD: standard deviation; SEM: standard error mean; vs, versus; Zn2+: zinc ion; Z-Phe: Z-Phe-Tyt(tBu)-diazomethylketone; Z-VAD-FMK: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone.
- Published
- 2021
- Full Text
- View/download PDF
14. Supp_material_Bestion_et_al._review – Supplemental material for GNS561 acts as a potent anti-fibrotic and pro-fibrolytic agent in liver fibrosis through TGF-β1 inhibition
- Author
-
Eloïne Bestion, Jilkova, Zuzana Macek, Jean-Louis Mège, Novello, Marie, Keerthi Kurma, Seyedeh Tayebeh Ahmad Pour, Lalmanach, Gilles, Vanderlynden, Lise, Fizanne, Lionel, Bassissi, Firas, Madani Rachid, Tracz, Jennifer, Boursier, Jérôme, Courcambeck, Jérôme, Serdjebi, Cindy, Ansaldi, Christelle, Decaens, Thomas, Halfon, Philippe, and Brun, Sonia
- Subjects
FOS: Psychology ,110203 Respiratory Diseases ,FOS: Clinical medicine ,Cardiology ,170199 Psychology not elsewhere classified ,111702 Aged Health Care ,FOS: Health sciences ,110319 Psychiatry (incl. Psychotherapy) ,110306 Endocrinology ,110308 Geriatrics and Gerontology ,111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified ,110904 Neurology and Neuromuscular Diseases - Abstract
Supplemental material, Supp_material_Bestion_et_al._review for GNS561 acts as a potent anti-fibrotic and pro-fibrolytic agent in liver fibrosis through TGF-β1 inhibition by Eloïne Bestion, Zuzana Macek Jilkova, Jean-Louis Mège, Marie Novello, Keerthi Kurma, Seyedeh Tayebeh Ahmad Pour, Gilles Lalmanach, Lise Vanderlynden, Lionel Fizanne, Firas Bassissi, Madani Rachid, Jennifer Tracz, Jérôme Boursier, Jérôme Courcambeck, Cindy Serdjebi, Christelle Ansaldi, Thomas Decaens, Philippe Halfon and Sonia Brun in Therapeutic Advances in Chronic Disease
- Published
- 2020
- Full Text
- View/download PDF
15. GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions
- Author
-
Brun, Sonia, primary, Raymond, Eric, additional, Bassissi, Firas, additional, Jilkova, Zuzana Macek, additional, Mezouar, Soraya, additional, Rachid, Madani, additional, Novello, Marie, additional, Tracz, Jennifer, additional, Hamaï, Ahmed, additional, Lalmanach, Gilles, additional, Vanderlynden, Lise, additional, Bestion, Eloïne, additional, Legouffe, Raphael, additional, Stauber, Jonathan, additional, Schubert, Thomas, additional, Plach, Maximilian G., additional, Courcambeck, Jérôme, additional, Drouot, Cyrille, additional, Jacquemot, Guillaume, additional, Serdjebi, Cindy, additional, Roth, Gael, additional, Baudoin, Jean-Pierre, additional, Ansaldi, Christelle, additional, Decaens, Thomas, additional, and Halfon, Philippe, additional
- Published
- 2020
- Full Text
- View/download PDF
16. GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions.
- Author
-
Brun, Sonia, Bestion, Eloïne, Raymond, Eric, Bassissi, Firas, Jilkova, Zuzana Macek, Mezouar, Soraya, Rachid, Madani, Novello, Marie, Tracz, Jennifer, Hamaï, Ahmed, Lalmanach, Gilles, Vanderlynden, Lise, Legouffe, Raphael, Stauber, Jonathan, Schubert, Thomas, Plach, Maximilian G., Courcambeck, Jérôme, Drouot, Cyrille, Jacquemot, Guillaume, and Serdjebi, Cindy
- Subjects
HEPATOCELLULAR carcinoma ,TUBULINS ,CATHEPSIN B ,MAGNETIC resonance imaging ,POLY ADP ribose ,MEMBRANE proteins ,CYCLINS ,ANNEXINS - Abstract
Hepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two hepatocellular carcinoma in vivo models. We showed that due to its lysosomotropic properties, GNS561 could reach and specifically inhibited its enzyme target, PPT1 (palmitoyl-protein thioesterase 1), resulting in lysosomal unbound Zn
2+ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of MTOR (mechanistic target of rapamycin kinase), lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, for which a global phase 1b clinical trial in liver cancers was just successfully achieved, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment. Abbreviations: ANXA5:annexin A5; ATCC: American type culture collection; BafA1: bafilomycin A1 ; BSA: bovine serum albumin; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CCND1: cyclin D1; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; CQ: chloroquine; iCCA: intrahepatic cholangiocarcinoma; DEN: diethylnitrosamine; DMEM: Dulbelcco's modified Eagle medium; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCC: hepatocellular carcinoma; HCQ: hydroxychloroquine; HDSF: hexadecylsulfonylfluoride; IC50 : mean half-maximal inhibitory concentration; LAMP: lysosomal associated membrane protein; LC3-II: phosphatidylethanolamine-conjugated form of MAP1LC3; LMP: lysosomal membrane permeabilization; MALDI: matrix assisted laser desorption ionization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation Ki-67; MTOR: mechanistic target of rapamycin kinase; MRI: magnetic resonance imaging; NH4 Cl: ammonium chloride; NtBuHA: N-tert-butylhydroxylamine; PARP: poly(ADP-ribose) polymerase; PBS: phosphate-buffered saline; PPT1: palmitoyl-protein thioesterase 1; SD: standard deviation; SEM: standard error mean; vs, versus; Zn2+ : zinc ion; Z-Phe: Z-Phe-Tyt(tBu)-diazomethylketone; Z-VAD-FMK: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
17. GNS561 acts as a potent anti-fibrotic and pro-fibrolytic agent in liver fibrosis through TGF-β1 inhibition
- Author
-
Bestion, Eloïne, primary, Jilkova, Zuzana Macek, additional, Mège, Jean-Louis, additional, Novello, Marie, additional, Kurma, Keerthi, additional, Pour, Seyedeh Tayebeh Ahmad, additional, Lalmanach, Gilles, additional, Vanderlynden, Lise, additional, Fizanne, Lionel, additional, Bassissi, Firas, additional, Rachid, Madani, additional, Tracz, Jennifer, additional, Boursier, Jérôme, additional, Courcambeck, Jérôme, additional, Serdjebi, Cindy, additional, Ansaldi, Christelle, additional, Decaens, Thomas, additional, Halfon, Philippe, additional, and Brun, Sonia, additional
- Published
- 2020
- Full Text
- View/download PDF
18. AMP-activated Protein Kinase α2 Subunit Is Required for the Preservation of Hepatic Insulin Sensitivity by n-3 Polyunsaturated Fatty Acids
- Author
-
Jelenik, Tomas, Rossmeisl, Martin, Kuda, Ondrej, Jilkova, Zuzana Macek, Medrikova, Dasa, Kus, Vladimir, Hensler, Michal, Janovska, Petra, Miksik, Ivan, Baranowski, Marcin, Gorski, Jan, Hébrard, Sophie, Jensen, Thomas E., Flachs, Pavel, Hawley, Simon, Viollet, Benoit, and Kopecky, Jan
- Published
- 2010
- Full Text
- View/download PDF
19. GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma viamodulation of lysosomal functions
- Author
-
Brun, Sonia, Bestion, Eloïne, Raymond, Eric, Bassissi, Firas, Jilkova, Zuzana Macek, Mezouar, Soraya, Rachid, Madani, Novello, Marie, Tracz, Jennifer, Hamaï, Ahmed, Lalmanach, Gilles, Vanderlynden, Lise, Legouffe, Raphael, Stauber, Jonathan, Schubert, Thomas, Plach, Maximilian G., Courcambeck, Jérôme, Drouot, Cyrille, Jacquemot, Guillaume, Serdjebi, Cindy, Roth, Gael, Baudoin, Jean-Pierre, Ansaldi, Christelle, Decaens, Thomas, and Halfon, Philippe
- Abstract
ABSTRACTHepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two hepatocellular carcinoma in vivo models. We showed that due to its lysosomotropic properties, GNS561 could reach and specifically inhibited its enzyme target, PPT1 (palmitoyl-protein thioesterase 1), resulting in lysosomal unbound Zn2+accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of MTOR (mechanistic target of rapamycin kinase), lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, for which a global phase 1b clinical trial in liver cancers was just successfully achieved, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment.Abbreviations: ANXA5:annexin A5; ATCC: American type culture collection; BafA1: bafilomycin A1; BSA: bovine serum albumin; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CCND1: cyclin D1; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; CQ: chloroquine; iCCA: intrahepatic cholangiocarcinoma; DEN: diethylnitrosamine; DMEM: Dulbelcco’s modified Eagle medium; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCC: hepatocellular carcinoma; HCQ: hydroxychloroquine; HDSF: hexadecylsulfonylfluoride; IC50: mean half-maximal inhibitory concentration; LAMP: lysosomal associated membrane protein; LC3-II: phosphatidylethanolamine-conjugated form of MAP1LC3; LMP: lysosomal membrane permeabilization; MALDI: matrix assisted laser desorption ionization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation Ki-67; MTOR: mechanistic target of rapamycin kinase; MRI: magnetic resonance imaging; NH4Cl: ammonium chloride; NtBuHA: N-tert-butylhydroxylamine; PARP: poly(ADP-ribose) polymerase; PBS: phosphate-buffered saline; PPT1: palmitoyl-protein thioesterase 1; SD: standard deviation; SEM: standard error mean; vs, versus; Zn2+: zinc ion; Z-Phe: Z-Phe-Tyt(tBu)-diazomethylketone; Z-VAD-FMK: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone.
- Published
- 2022
- Full Text
- View/download PDF
20. Abstract 3717: Animal model of cirrhosis with hepatocellular carcinoma: A reliable tool for testing new therapies
- Author
-
Kurma, Keerthi, primary, Jilkova, Zuzana Macek, additional, Marche, Patrice N., additional, Sturm, Nathalie, additional, Lerat, Hervé, additional, and Decaens, Thomas, additional
- Published
- 2019
- Full Text
- View/download PDF
21. GNS561 acts as a potent anti-fibrotic and pro-fibrolytic agent in liver fibrosis through TGF-β1 inhibition.
- Author
-
Bestion, Eloïne, Jilkova, Zuzana Macek, Mège, Jean-Louis, Novello, Marie, Kurma, Keerthi, Pour, Seyedeh Tayebeh Ahmad, Lalmanach, Gilles, Vanderlynden, Lise, Fizanne, Lionel, Bassissi, Firas, Rachid, Madani, Tracz, Jennifer, Boursier, Jérôme, Courcambeck, Jérôme, Serdjebi, Cindy, Ansaldi, Christelle, Decaens, Thomas, Halfon, Philippe, and Brun, Sonia
- Abstract
Background: Hepatic fibrosis is the result of chronic liver injury that can progress to cirrhosis and lead to liver failure. Nevertheless, there are no anti-fibrotic drugs licensed for human use. Here, we investigated the anti-fibrotic activity of GNS561, a new lysosomotropic molecule with high liver tropism. Methods: The anti-fibrotic effect of GNS561 was determined in vitro using LX-2 hepatic stellate cells (HSCs) and primary human HSCs by studying cell viability, activity of caspases 3/7, autophagic flux, cathepsin maturation and activity, HSC activation and transforming growth factor-β1 (TGF-β1) maturation and signaling. The contribution of GNS561 lysosomotropism to its anti-fibrotic activity was assessed by increasing lysosomal pH. The potency of GNS561 on fibrosis was evaluated in vivo in a rat model of diethylnitrosamine-induced liver fibrosis. Results: GNS561 significantly decreased cell viability and promoted apoptosis. Disrupting the lysosomal pH gradient impaired its pharmacological effects, suggesting that GNS561 lysosomotropism mediated cell death. GNS561 impaired cathepsin activity, leading to defective TGF-β1 maturation and autophagic processes. Moreover, GNS561 decreased HSC activation and extracellular matrix deposition by downregulating TGF-β1/Smad and mitogen-activated proteine kinase signaling and inducing fibrolysis. Finally, oral administration of GNS561 (15 mg/kg per day) was well tolerated and attenuated diethylnitrosamine-induced liver fibrosis in this rat model (decrease of collagen deposition and of pro-fibrotic markers and increase of fibrolysis). Conclusion: GNS561 is a new potent lysosomotropic compound that could represent a valid medicinal option for hepatic fibrosis treatment through both its anti-fibrotic and its pro-fibrolytic effects. In addition, this study provides a rationale for targeting lysosomes as a promising therapeutic strategy in liver fibrosis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
22. Combination of AKT inhibitor ARQ 092 and sorafenib potentiates inhibition of tumor progression in cirrhotic rat model of hepatocellular carcinoma
- Author
-
Jilkova, Zuzana Macek, primary, Kuyucu, Ayca Zeybek, additional, Kurma, Keerthi, additional, Ahmad Pour, Séyédéh Tayébéh, additional, Roth, Gaël S., additional, Abbadessa, Giovanni, additional, Yu, Yi, additional, Schwartz, Brian, additional, Sturm, Nathalie, additional, Marche, Patrice N., additional, Hainaut, Pierre, additional, and Decaens, Thomas, additional
- Published
- 2018
- Full Text
- View/download PDF
23. Abstract 5124: GNS561 a new quinoline derivative inhibits the growth of hepatocellular carcinoma in a cirrhotic rat and human PDX orthotopic mouse models
- Author
-
BASSISSI, Firas, primary, Jilkova, Zuzana Macek, additional, Brun, Sonia, additional, Courcambeck, Jerome, additional, Tracz, Jennifer, additional, Kurma, Keerthi, additional, Roth, Gaël S., additional, Khaldi, Cindy, additional, Chaimbault, Corinne, additional, Quentin, Benoit, additional, Asseraf, Emilie, additional, Beret, Antoine, additional, Raymond, Eric, additional, Halfon, Philippe, additional, and Decaens, Thomas, additional
- Published
- 2017
- Full Text
- View/download PDF
24. Unmasking Differential Effects of Rosiglitazone and Pioglitazone in the Combination Treatment with n-3 Fatty Acids in Mice Fed a High-Fat Diet
- Author
-
Kus, Vladimir, primary, Flachs, Pavel, additional, Kuda, Ondrej, additional, Bardova, Kristina, additional, Janovska, Petra, additional, Svobodova, Michaela, additional, Jilkova, Zuzana Macek, additional, Rossmeisl, Martin, additional, Wang-Sattler, Rui, additional, Yu, Zhonghao, additional, Illig, Thomas, additional, and Kopecky, Jan, additional
- Published
- 2011
- Full Text
- View/download PDF
25. The inhibition of fat cell proliferation by n-3 fatty acids in dietary obese mice
- Author
-
Hensler, Michal, primary, Bardova, Kristina, additional, Jilkova, Zuzana Macek, additional, Wahli, Walter, additional, Meztger, Daniel, additional, Chambon, Pierre, additional, Kopecky, Jan, additional, and Flachs, Pavel, additional
- Published
- 2011
- Full Text
- View/download PDF
26. Metabolic Effects of n-3 PUFA as Phospholipids Are Superior to Triglycerides in Mice Fed a High-Fat Diet: Possible Role of Endocannabinoids.
- Author
-
Rossmeisl, Martin, Jilkova, Zuzana Macek, Kuda, Ondrej, Jelenik, Tomas, Medrikova, Dasa, Stankova, Barbora, Kristinsson, Björn, Haraldsson, Gudmundur G., Svensen, Harald, Stoknes, Iren, Sjövall, Peter, Magnusson, Ylva, Balvers, Michiel G. J., Verhoeckx, Kitty C. M., Tvrzicka, Eva, Bryhn, Morten, and Kopecky, Jan
- Subjects
- *
TRIGLYCERIDES , *METABOLISM , *FATTY acids , *PHOSPHOLIPIDS , *CANNABINOIDS , *HALLUCINOGENIC drugs - Abstract
Background: n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the risk of cardiovascular disease and can ameliorate many of obesity-associated disorders. We hypothesised that the latter effect will be more pronounced when DHA/EPA is supplemented as phospholipids rather than as triglycerides. Methodology/Principal Findings: In a 'prevention study', C57BL/6J mice were fed for 9 weeks on either a corn oil-based high-fat obesogenic diet (cHF; lipids ∼35% wt/wt), or cHF-based diets in which corn oil was partially replaced by DHA/EPA, admixed either as phospholipids or triglycerides from marine fish. The reversal of obesity was studied in mice subjected to the preceding cHF-feeding for 4 months. DHA/EPA administered as phospholipids prevented glucose intolerance and tended to reduce obesity better than triglycerides. Lipemia and hepatosteatosis were suppressed more in response to dietary phospholipids, in correlation with better bioavailability of DHA and EPA, and a higher DHA accumulation in the liver, white adipose tissue (WAT), and muscle phospholipids. In dietary obese mice, both DHA/EPA concentrates prevented a further weight gain, reduced plasma lipid levels to a similar extent, and tended to improve glucose tolerance. Importantly, only the phospholipid form reduced plasma insulin and adipocyte hypertrophy, while being more effective in reducing hepatic steatosis and low-grade inflammation of WAT. These beneficial effects were correlated with changes of endocannabinoid metabolome in WAT, where phospholipids reduced 2-arachidonoylglycerol, and were more effective in increasing anti-inflammatory lipids such as N-docosahexaenoylethanolamine. Conclusions/Significance: Compared with triglycerides, dietary DHA/EPA administered as phospholipids are superior in preserving a healthy metabolic profile under obesogenic conditions, possibly reflecting better bioavalability and improved modulation of the endocannabinoid system activity in WAT. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
27. NASH limits anti-tumour surveillance in immunotherapy-treated HCC
- Author
-
Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K, Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M, Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D'Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K, Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M, Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G, Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G, Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E, Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz De Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-Francois, Marron, Thomas U, Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N, Decaens, Thomas, Pinato, David J, Rad, Roland, Mertens, Joachim C, Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M, Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M, and Heikenwalder, Mathias
- Subjects
Male ,Carcinoma, Hepatocellular ,Carcinogenesis ,Tumor Necrosis Factor-alpha ,Liver Neoplasms ,Programmed Cell Death 1 Receptor ,CD8-Positive T-Lymphocytes ,digestive system diseases ,B7-H1 Antigen ,3. Good health ,Mice ,Liver ,Non-alcoholic Fatty Liver Disease ,Disease Progression ,Animals ,Humans ,Immunotherapy - Abstract
Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
28. NASH limits anti-tumour surveillance in immunotherapy-treated HCC
- Author
-
Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K, Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M, Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D'Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K, Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M, Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G, Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G, Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E, Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz de Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-François, Marron, Thomas U, Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N, Decaens, Thomas, Pinato, David J, Rad, Roland, Mertens, Joachim C, Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M, Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M, and Heikenwalder, Mathias
- Subjects
610 Medicine & health ,digestive system diseases ,3. Good health - Abstract
Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
29. NASH limits anti-tumour surveillance in immunotherapy-treated HCC
- Author
-
Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K., Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M., Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D’Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K., Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M., Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G., Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G., Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E., Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz De Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-Francois, Marron, Thomas U., Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N., Decaens, Thomas, Pinato, David J., Rad, Roland, Mertens, Joachim C., Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M., Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M., and Heikenwalder, Mathias
- Subjects
631/67 ,article ,631/250/251 ,digestive system diseases ,3. Good health ,13/31 ,13/2 ,14/32 ,13/1 ,14/34 ,13/21 ,13/51 ,14/63 ,59/57 ,64/60 ,14/19 ,14/35 - Abstract
Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6, 7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.