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HMGB1 and Gasdermin D: intratumoral targets to improve the response to cancer immunotherapy

English title HMGB1 and Gasdermin D: intratumoral targets to improve the response to cancer immunotherapy
Applicant Bourquin Carole
Number 182317
Funding scheme Project funding (Div. I-III)
Research institution Université de Geneve
Institution of higher education University of Geneva - GE
Main discipline Experimental Cancer Research
Start/End 01.01.2019 - 31.12.2022
Approved amount 700'000.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Immunology, Immunopathology

Keywords (5)

Innate immunity; Immune checkpoint inhibitors; Tumor immunology; Tumor microenvironment; Cancer

Lay Summary (French)

Lead
Les développements récents en immunothérapie ont permis de grands progrès dans le traitement du cancer, mais de nombreux patients ne répondent toujours pas à cette approche thérapeutique. Ce projet étudiera comment certains facteurs produits par les tumeurs affectent la réponse à l'immunothérapie.
Lay summary

Contenu et objectifs du travail de recherche

Alors que l'immunothérapie permet de guérir certains patients atteints du cancer, d'autres patients ne répondent pas à ce type de thérapie. Les facteurs permettant de prédire la réponse au traitement sont mal connus, bien que des études récentes aient montré que certaines molécules produites par le cancer lui-même peuvent influencer cette réponse. Le projet contribuera à clarifier ces aspects.

Nous étudierons comment la production par le cancer de certaines molécules affecte le système  immunitaire et nous en éluciderons les mécanismes au niveau moléculaire et cellulaire. Nous rechercherons ensuite comment ces molécules d'origine tumorale impactent la réponse à un traitement d'immunothérapie et si leur présence a une valeur prédictive pour l'efficacité du traitement. Finalement, nous testerons la capacité de substances pharmacologiques ciblant ces molécules à augmenter la réponse immunitaire antitumorale.  Pour améliorer la spécificité de ces traitements, nous utiliserons des nanoparticules qui serviront de transporteurs de médicaments.

 

Contexte scientifique et clinique

Le projet relève de la recherche fondamentale. Pour développer et améliorer les traitements contre le cancer, il est important de bien comprendre d'abord les mécanismes physiopathologiques. Les découvertes attendues dans le cadre de ce projet pourront potentiellement guider la recherche au niveau clinique pour l'immunothérapie du cancer.

Direct link to Lay Summary Last update: 12.10.2018

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
156372 RLR/TLR combination therapy: Mechanisms of T-cell recruitment into gastric tumors 01.06.2015 Project funding (Div. I-III)
137087 Cell Migration 01.09.2011 ProDoc
141849 NCCR Bio-Inspired Materials: Center for Bio-Inspired Stimuli-Responsive Materials (phase I) 01.06.2014 National Centres of Competence in Research (NCCRs)
141773 ProDoc Cell Migration Research Module 3: Soluble factors in Cell Migration 01.10.2012 ProDoc
156871 Understanding the interaction of nanoparticles with B lymphocytes in vitro and in vivo 01.02.2015 Project funding (Div. I-III)

Abstract

BackgroundCancer immunotherapy has recently made a breakthrough with the advent of immune checkpoint inhibitors, but only a minority of patients currently benefits from these treatments. One reason is that many tumors are poorly infiltrated by immune cells, which renders them resistant to checkpoint blockade approaches. The precise factors that trigger a specific immunological landscape in cancer are still unclear, although tumor-intrinsic factors, including the genetic makeup of the tumor, have been implicated. We propose to investigate how the intratumoral expression of selected proteins involved in innate immunity affects immune cell infiltration and the development of anticancer responses.Working hypothesis and aimsWe have recently demonstrated that the genetic downregulation of tumor-intrinsic molecules involved in innate immunity enhances immune cell recruitment to the tumor, increases T-cell numbers in the spleen and blocks tumor progression. Here we will study the mechanisms by which these molecules impact the antitumor immune response and shape the immune landscape.Specifically, we aim to:•Characterize the effect of intratumoral production of molecules involved in innate immunity on the immune landscape•Elucidate the mechanisms by which these proteins control the antitumor immune response•Demonstrate the predictive and therapeutic implications of these findings for immunotherapy with checkpoint inhibitors •Use our expertise in nanoparticle-based drug delivery to augment the specificity of therapeutic approaches targeting these proteinsExpected valueThe output from this project will lead to a better understanding of how intratumoral effectors of innate immunity affect the immune landscape and how this knowledge can be exploited for pharmacological intervention. Our results will be highly relevant to improve the outcome of immunotherapeutic strategies to treat cancer. The insights obtained in this project may guide the design of future translational studies with immune checkpoint inhibitors.
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