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RLR/TLR combination therapy: Mechanisms of T-cell recruitment into gastric tumors

English title RLR/TLR combination therapy: Mechanisms of T-cell recruitment into gastric tumors
Applicant Bourquin Carole
Number 156372
Funding scheme Project funding (Div. I-III)
Research institution Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Experimental Cancer Research
Start/End 01.06.2015 - 31.12.2018
Approved amount 550'000.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Immunology, Immunopathology

Keywords (4)

Immunotherapy; Cancer; Tumor immunology; T cells

Lay Summary (French)

Lead
Activer les défenses de notre corps contre le cancer: comment guider les cellules immunitaires vers la tumeur?
Lay summary

Dans la recherche de stratégies plus efficaces pour le traitement du cancer, l’immunothérapie est actuellement l’une des voies les plus prometteuses. Cette approche implique l’activation des défenses propres à l’organisme pour détruire les cellules cancéreuses et les tissus de soutien de la tumeur. De nombreux groupes de recherche ont développé avec succès des techniques pour produire un grand nombre de cellules immunitaires dirigées contre la tumeur, comme des lymphocytes T. Mais le manque de recrutement de ces cellules dans la tumeur elle-même représente souvent un obstacle majeur au succès clinique. Dans ce projet nous recherchons de nouvelles cibles thérapeutiques pour encourager la migration des cellules T vers les tumeurs gastrointestinales. En utilisant un protocole d’immunothérapie développé dans notre laboratoire, nous étudions les mécanismes par lesquels ce traitement augmente le recrutement des cellules T dans les tumeurs de l’estomac. Notre but est de découvrir de nouveaux facteurs qui stimulent la migration des lymphocytes T. Ces facteurs pourront ensuite servir de cible thérapeutique pour augmenter l’efficacité des immunothérapies basées sur les lymphocytes T.

Direct link to Lay Summary Last update: 17.03.2015

Lay Summary (English)

Lead
Activating the body’s own defenses against cancer: how can we guide immune cells into the tumor?
Lay summary

In the search for more efficient treatment strategies for cancer, immunotherapy is one of the most promising avenues to date. This approach involves the activation of the body’s own immune defenses to find and destroy cancer cells and cancer-supporting tissue. Many research groups have successfully developed techniques to produce large numbers of anti-cancer immune cells, such as T lymphocytes, but the lack of recruitment of these cells to the tumor itself is often a major obstacle for clinical success. In this project we will search for new therapeutic targets to promote the migration of anti-tumor T cells into gastrointestinal tumors. Using an efficient immunotherapy protocol developed in our laboratory, we will investigate the mechanisms by which this treatment enhances T-cell recruitment into gastric tumors. We thus aim to discover new factors that promote T-cell migration. These factors may then serve as therapeutic targets to enhance the efficacy of T-cell based immunotherapy.  

Direct link to Lay Summary Last update: 17.03.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Amphiphilic nanoparticle delivery enhances the anticancer efficacy of a TLR7 ligand via local immune activation
Mottas Inès, Bekdemir Ahmet, Cereghetti Alessandra, Spagnuolo Lorenzo, Yang Yu-Sang Sabrina, Müller Marie, Irvine Darrell J., Stellacci Francesco, Bourquin Carole (2019), Amphiphilic nanoparticle delivery enhances the anticancer efficacy of a TLR7 ligand via local immune activation, in Biomaterials, 190-191, 111-120.
Engineered hybrid spider silk particles as delivery system for peptide vaccines
Lucke Matthias, Mottas Inès, Herbst Tina, Hotz Christian, Römer Lin, Schierling Martina, Herold Heike M., Slotta Ute, Spinetti Thibaud, Scheibel Thomas, Winter Gerhard, Bourquin Carole, Engert Julia (2018), Engineered hybrid spider silk particles as delivery system for peptide vaccines, in Biomaterials, 172, 105-115.
NAB2 is a novel immune stimulator of MDA-5 that promotes a strong type I interferon response
Oberson Anne, Spagnuolo Lorenzo, Puddinu Viola, Barchet Winfried, Rittner Karola, Bourquin Carole (2018), NAB2 is a novel immune stimulator of MDA-5 that promotes a strong type I interferon response, in Oncotarget, 9(5), 5641-5651.
Polymer-based nanoparticles loaded with a TLR7 ligand to target the lymph node for immunostimulation
Widmer Jérôme, Thauvin Cédric, Mottas Inès, Nguyen Van Nga, Delie Florence, Allémann Eric, Bourquin Carole (2018), Polymer-based nanoparticles loaded with a TLR7 ligand to target the lymph node for immunostimulation, in International Journal of Pharmaceutics, 535(1-2), 444-451.
A rapid screening method to evaluate the impact of nanoparticles on macrophages
Mottas Inès, Milosevic Ana, Petri-Fink Alke, Rothen-Rutishauser Barbara, Bourquin Carole (2017), A rapid screening method to evaluate the impact of nanoparticles on macrophages, in Nanoscale, 9(7), 2492-2504.
Antimicrobial silver-filled silica nanorattles with low immunotoxicity in dendritic cells
Priebe Magdalena, Widmer Jérôme, Suhartha Löwa Nina, Abram Sarah-Luise, Mottas Inès, Woischnig Anne-Kathrin, Brunetto Priscilla S., Khanna Nina, Bourquin Carole, Fromm Katharina M. (2017), Antimicrobial silver-filled silica nanorattles with low immunotoxicity in dendritic cells, in Nanomedicine: Nanotechnology, Biology and Medicine, 13(1), 11-22.
Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses
Hotz Christian, Treinies Marina, Mottas Ines, Rötzer Laurin C., Oberson Anne, Spagnuolo Lorenzo, Perdicchio Maurizio, Spinetti Thibaud, Herbst Tina, Bourquin Carole (2016), Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses, in OncoImmunology, 5(11), e1232219-e1232219.
TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function
Spinetti Thibaud, Spagnuolo Lorenzo, Mottas Inès, Secondini Chiara, Treinies Marina, Rüegg Curzio, Hotz Christian, Bourquin Carole (2016), TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function, in OncoImmunology, 5(11), e1230578-e1230578.
Immune response to functionalized mesoporous silica nanoparticles for targeted drug delivery
Heidegger Simon, Gößl Dorothée, Schmidt Alexandra, Niedermayer Stefan, Argyo Christian, Endres Stefan, Bein Thomas, Bourquin Carole (2016), Immune response to functionalized mesoporous silica nanoparticles for targeted drug delivery, in Nanoscale, 8(2), 938-948.
Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression
Anz David, Rapp Moritz, Eiber Stephan, Koelzer Viktor H., Thaler Raffael, Haubner Sascha, Knott Max, Nagel Sarah, Golic Michaela, Wiedemann Gabriela M., Bauernfeind Franz, Wurzenberger Cornelia, Hornung Veit, Scholz Christoph, Mayr Doris, Rothenfusser Simon, Endres Stefan, Bourquin Carole (2015), Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression, in Cancer Research, 75(21), 4483-4493.
TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection
Hotz Christian, Roetzer Laurin C., Huber Thomas, Sailer Andreas, Oberson Anne, Treinies Marina, Heidegger Simon, Herbst Tina, Endres Stefan, Bourquin Carole (2015), TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection, in The Journal of Immunology, 195(9), 4387-4395.

Collaboration

Group / person Country
Types of collaboration
Prof. Darrell Irvine, Massachusetts Institute of Technology United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
ProDoc Cell Migration Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Prof. W. Zimmermann, University of Munich Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. F. Stellaci, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Thomas Scheibel, University of Bayreuth Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Curzio Rüegg, University of Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
National Center of Competence in Research "Bio-inspired Materials" Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Eric Allémann, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
BayImmuNet Immunotherapy Network Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
BIC – the Bern Immunology Club Talk given at a conference “HMGB1: Controlling B-cell trafficking in the Peyer’s patches” 26.09.2018 Bern, Switzerland Bourquin Carole;
6th Cell Migration Retreat Talk given at a conference “Baseline characterization of the tumor microenvironment in different mouse tumor models” 05.09.2018 Gerzensee, Switzerland Taskoparan Betül; Steinhoff Nathalie; Bourquin Carole;
6th Cell Migration Retreat Poster “Impact of glucocorticoids on anti-cancer immune response" 05.09.2018 Gerzensee, Switzerland Bourquin Carole; Taskoparan Betül; Poinot Hélène; Steinhoff Nathalie;
6th Cell Migration Retreat Talk given at a conference “A new role for HMGB1” 05.09.2018 Gerzensee, Switzerland Steinhoff Nathalie; Taskoparan Betül; Poinot Hélène; Bourquin Carole;
32nd Seminar in Pharmaceutical Sciences, From an idea to the patient Talk given at a conference “Impact of glucocorticoids on anti-tumor immunity” 27.08.2018 Zermatt, Switzerland Taskoparan Betül; Poinot Hélène; Bourquin Carole;
32nd Seminar in Pharmaceutical Sciences, From an idea to the patient Talk given at a conference “Fighting cancer with spider silk” 27.08.2018 Zermatt, Switzerland Bourquin Carole; Taskoparan Betül; Poinot Hélène;
32nd Seminar in Pharmaceutical Sciences, From an idea to the patient Talk given at a conference “pH-responsive mesoporous silica nanoparticles as delivery system for cancer vaccines” 27.08.2018 Zermatt, Switzerland Bourquin Carole; Taskoparan Betül; Poinot Hélène;
European Congress on Biotechnology (ECB 2018) Talk given at a conference “How not to prepare your CV” 03.07.2018 Geneva, Switzerland Bourquin Carole;
27th Immunology Day Talk given at a conference "A new role for HMGB1: Controlling B-cell trafficking in the Peyer’s patches” 20.06.2018 Geneva, Switzerland Bourquin Carole; Poinot Hélène; Taskoparan Betül;
1st Symposium of the Centre for Translational Research in Oncohaematology, Campus Biotech Talk given at a conference “The Immunopharmacology of cancer" 18.06.2018 Geneva, Switzerland Taskoparan Betül; Gül Ersin; Bourquin Carole;
5th Cell Migration PhD Retreat Poster “Tumor microenvironment-dependent inhibition of leukocyte infiltration to tumors: insights from a model of gastric cancer” 22.09.2017 Bellinzona, Switzerland Gül Ersin; Steinhoff Nathalie; Taskoparan Betül; Bourquin Carole;
5th Cell Migration PhD Retreat Poster “Gasdermin D, The New Killer” 22.09.2017 Bellinzona, Switzerland Bourquin Carole; Steinhoff Nathalie; Taskoparan Betül; Gül Ersin;
5th Cell Migration PhD Retreat Poster “Tumor microenvironment-dependent inhibition of leukocyte infiltration to tumors: insights from a model of gastric cancer” 22.09.2017 Bellinzona, Switzerland Gül Ersin; Bourquin Carole; Steinhoff Nathalie; Taskoparan Betül;
The 3rd CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference Poster “Tumor microenvironment-dependent inhibition of leukocyte infiltration to tumors: insights from a model of gastric cancer” 06.09.2017 Mainz, Germany Steinhoff Nathalie; Bourquin Carole; Taskoparan Betül;
The 3rd CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference Poster “HMGB1 regulates CXCL12-dependent recruitment of MDSCs to tumors” 06.09.2017 Mainz, Germany Bourquin Carole; Taskoparan Betül; Steinhoff Nathalie;
31st Seminar in Pharmaceutical Sciences, PhD program in Pharmaceutical Sciences : Pharmacology from Bench to Bedside Talk given at a conference “How not to prepare your CV” 31.08.2017 Zermatt, Switzerland Bourquin Carole;
Center for Translational Research in Onco-hematology, University of Geneva Talk given at a conference “How to harness myeloid-derived suppressor cells” 18.05.2017 Geneva, Switzerland Bourquin Carole;
Collège des professeurs de la Faculté de Médecine, Université de Genève Individual talk “Comment prédire l’effet des nanoparticules sur notre système immunitaire ?” 09.05.2017 Geneva, Switzerland Bourquin Carole;
Immunology Club Individual talk "Innate immune activation for cancer therapy” 31.03.2017 Geneva, Switzerland Bourquin Carole;
EPFL Individual talk “How to predict the impact of nanoparticles on the immune system” 15.03.2017 Lausanne, Switzerland Bourquin Carole;
Immunofest 2016 Talk given at a conference “Reprogramming innate immune signalling to improve cancer immunotherapy” 29.09.2016 Munich, Germany Bourquin Carole;
German Pharm-Tox Summit 2016 Talk given at a conference “Immunostimulation for cancer therapy: timing is everything” 29.02.2016 Berlin, Germany Bourquin Carole;
Transgene SA Individual talk “RLR and TLR-based cancer immunotherapy: Timing is everything!” 25.01.2016 Strasbourg, France Bourquin Carole;


Self-organised

Title Date Place
6th Cell Migration Retreat 05.09.2018 Gerzensee, Switzerland
European Congress on Biotechnology (ECB 2018), Symposium 21: Formulation, Package and Delivery 01.07.2018 Geneva, Switzerland
1st symposium of the Center for Research in Translational Onco-Hematology 18.06.2018 Geneva, Switzerland
Life Sciences Switzerland (LS2) Annual Meeting 2018: Symposium de la Société Suisse de Pharmacologie Expérimentale 12.02.2018 Lausanne, Switzerland
31st Seminar in Pharmaceutical Sciences, PhD program in Pharmaceutical Sciences : Pharmacology from Bench to Bedside 28.08.2017 Zermatt, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Leçon inaugurale Talk 30.03.2017 Geneva, Switzerland Bourquin Carole;
Inauguration de l’EPGL : participation à la table ronde: "L’avenir des sciences pharmaceutiques fondamentales" Workshop 20.03.2017 Geneva, Switzerland Bourquin Carole;
Nano World Cancer Day 2017 Talk 02.02.2017 Geneva, Switzerland Bourquin Carole;
Journée portes ouvertes lors de l’inauguration des nouveaux locaux de l’EPGL Performances, exhibitions (e.g. for education institutions) 21.11.2016 Geneva, Switzerland Bourquin Carole;


Self-organised

Title Date Place
Organisation d'un atelier pratique pour classes d'école primaire "Développons un médicament contre le cancer" 20.04.2018 Geneva, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: radio, television "Des particules en soie d'araignée pour guérir le cancer" RTS, émission CQFD Western Switzerland 2018
Media relations: print media, online media "La soie d'araignée pour des vaccins d'un nouveau genre" Nombreux médias International Western Switzerland German-speaking Switzerland 2018
Media relations: print media, online media Organisation d'un atelier pratique école primaire "Développons un médicament contre le cancer" PharmaJournal Western Switzerland 2018
Talks/events/exhibitions "L’immunothérapie, une nouvelle stratégie contre le cancer" Western Switzerland 2017
Media relations: print media, online media "Narrowing the hunt for nanoparticles” NCCR Bio-Inspired Materials communication International German-speaking Switzerland Western Switzerland 2017
Media relations: print media, online media "Une méthode révolutionnaire pour sélectionner les nanoparticules les plus prometteuses en médecine" Nombreux médias International German-speaking Switzerland Western Switzerland 2017

Associated projects

Number Title Start Funding scheme
182317 HMGB1 and Gasdermin D: intratumoral targets to improve the response to cancer immunotherapy 01.01.2019 Project funding (Div. I-III)
137087 Cell Migration 01.09.2011 ProDoc
141773 ProDoc Cell Migration Research Module 3: Soluble factors in Cell Migration 01.10.2012 ProDoc
138284 Immunotherapy of gastric cancer: Enhancing T cell recruitment into tumors 01.01.2012 Project funding (Div. I-III)
141849 NCCR Bio-Inspired Materials: Center for Bio-Inspired Stimuli-Responsive Materials (phase I) 01.06.2014 National Centres of Competence in Research (NCCRs)

Abstract

Cancer immunotherapy has reached a breakthrough in 2013 with the advent of drugs based on immune checkpoint blockade. However, even the most effective treatment options in immunotherapy, including the adoptive transfer of tumor-specific T cells into patients, result in an objective clinical response in only a minority of patients. One reason may be that many tumors lack the ability to recruit cytotoxic T cells, which can render them resistant to current immunotherapy approaches. Strategies that reinforce the migration of T cells into tumors are therefore urgently needed to complement existing treatments that foster the antitumor effector function of T cells. In a model of gastric cancer, we have previously demonstrated that T cells do not infiltrate the tumors, even upon adoptive transfer of tumor-specific T cells. We have recently developed a treatment protocol with a combination of Rig-I-like receptor (RLR) and Toll-like receptor (TLR) ligands that induces strong innate immune activation and greatly enhances CD8 T-cell recruitment to the gastric tumors. We propose to study the mechanisms that support intratumoral T-cell accumulation in this model. Specifically, we aim to:•Discover new factors and pathways that foster T-cell migration into tumors•Combine RLR/TLR-based therapy with treatments targeting antitumoral T-cell function to further improve the outcome•Use our expertise in nanoparticle-based drug delivery to augment the specificity of RLR/TLR therapyThe output from this project will lead to a better understanding of how cytotoxic T cells infiltrate gastric tumors and how recruitment of these cells can be induced by pharmacologic intervention. This knowledge will be of high relevance for improving the outcome of immunotherapeutic strategies to treat gastric cancer and other gastrointestinal tumors. The insights obtained in this project may direct impact the design of future translational studies in cancer immunotherapy.
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