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Modulation of sialoglycans for cancer immunotherapy

English title Modulation of sialoglycans for cancer immunotherapy
Applicant Läubli Heinz-Philipp
Number 184720
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.04.2019 - 31.03.2022
Approved amount 329'288.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Immunology, Immunopathology

Keywords (5)

Siglec; Immune checkpoint; Sialidase; Cancer Immunotherapy; Sialic acid

Lay Summary (German)

Lead
Mit veränderten Zuckern das Immunsystem gegen Krebs aktivieren
Lay summary
Die vergangenen Jahre haben gezeigt, dass man mit Medikamenten das Immunsystem gegen Krebs aktivieren kann und teilweise bei Patienten mit fortgeschrittenen Krebserkrankungen der Krebs eliminiert und langfristig kontrolliert werden kann. Diese Medikamente, sogenannten Checkpoint-Inhibitoren führen dazu, dass vorher gelähmte Immunzellen den Krebs wieder erkennen und so angreifen können. Leider profitiert aktuell nur eine Minderheit der krebserkrankten Menschen von dieser Therapie und viele Tumorarten sind resistent dagegen.

In diesem Projekt versuchen wir das Immunsystem auf eine neue Art gegen den Krebs zu aktivieren. Viele Tumorzellen produzieren Zuckerketten auf der Oberfläche, die den Zucker Sialinsäure enthalten. Unsere früheren Arbeiten konnten zeigen, dass diese Sialinsäure-haltigen Zuckerketten auch die Immunzellen lähmen können. Dieses Projekt zielt nun daraufhin, Sialinsäure aus dem Tumor therapeutisch zu entfernen, um das Immunsystem wieder gegen den Tumor zu aktivieren. Ein Ansatz ist es, Enzyme zielgerichtet mit Antikörpern in den Tumor zu bringen, die dann die Sialinsäure aus den Zuckerstrukturen der Tumorzellen entfernen.

Wir hoffen mit diesem Ansatz, neuartige Krebsmedikamente zu entwickeln, die den Vorteil der Immuntherapie, nämlich langfristige Krebskontrolle auch bei fortgeschrittenen Tumorerkrankungen, für noch mehr Patienten verfügbar machen.
Direct link to Lay Summary Last update: 29.03.2019

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Targeted glycan degradation potentiates the anticancer immune response in vivo
Gray Melissa A., Stanczak Michal A., Mantuano Natália R., Xiao Han, Pijnenborg Johan F. A., Malaker Stacy A., Miller Caitlyn L., Weidenbacher Payton A., Tanzo Julia T., Ahn Green, Woods Elliot C., Läubli Heinz, Bertozzi Carolyn R. (2020), Targeted glycan degradation potentiates the anticancer immune response in vivo, in Nature Chemical Biology, 16(12), 1376-1384.
Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy
Rodrigues Mantuano Natalia, Natoli Marina, Zippelius Alfred, Läubli Heinz (2020), Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy, in Journal for ImmunoTherapy of Cancer, 8(2), e001222-e001222.
Hyperglycemia Enhances Cancer Immune Evasion by Inducing Alternative Macrophage Polarization through Increased O-GlcNAcylation
Rodrigues Mantuano Natália, Stanczak Michal A., Oliveira Isadora de Araújo, Kirchhammer Nicole, Filardy Alessandra A., Monaco Gianni, Santos Ronan Christian, Fonseca Agatha Carlos, Fontes Miguel, Bastos César de Souza, Dias Wagner B., Zippelius Alfred, Todeschini Adriane R., Läubli Heinz (2020), Hyperglycemia Enhances Cancer Immune Evasion by Inducing Alternative Macrophage Polarization through Increased O-GlcNAcylation, in Cancer Immunology Research, 8(10), 1262-1272.
Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer
Trüb Marta, Uhlenbrock Franziska, Claus Christina, Herzig Petra, Thelen Martin, Karanikas Vaios, Bacac Marina, Amann Maria, Albrecht Rosemarie, Ferrara-Koller Claudia, Thommen Daniela, Rothschield Sacha, Savic Prince Spasenija, Mertz Kirsten D, Cathomas Gieri, Rosenberg Robert, Heinzelmann-Schwarz Viola, Wiese Mark, Lardinois Didier, Umana Pablo, Klein Christian, Läubli Heinz, Kashyap Abhishek S, Zippelius Alfred (2020), Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer, in Journal for ImmunoTherapy of Cancer, 8(2), e000238-e000238.
The sialoglycan-Siglec glyco-immune checkpoint – a target for improving innate and adaptive anti-cancer immunity
Bärenwaldt Anne, Läubli Heinz (2019), The sialoglycan-Siglec glyco-immune checkpoint – a target for improving innate and adaptive anti-cancer immunity, in Expert Opinion on Therapeutic Targets, 23(10), 839-853.
Siglec-9 Regulates an Effector Memory CD8 + T-cell Subset That Congregates in the Melanoma Tumor Microenvironment
Haas Quentin, Boligan Kayluz Frias, Jandus Camilla, Schneider Christoph, Simillion Cedric, Stanczak Michal A., Haubitz Monika, Seyed Jafari Seyed Morteza, Zippelius Alfred, Baerlocher Gabriela M., Läubli Heinz, Hunger Robert E., Romero Pedro, Simon Hans-Uwe, von Gunten Stephan (2019), Siglec-9 Regulates an Effector Memory CD8 + T-cell Subset That Congregates in the Melanoma Tumor Microenvironment, in Cancer Immunology Research, 7(5), 707-718.

Abstract

The introduction of immune checkpoint inhibitors (ICI) into routine cancer therapy has changed the prognosis of cancer patients. Current ICI are blocking antibodies that target immune checkpoints including PD-1 and CTLA-4. ICI are the proof of principle that a dysfunctional immune system can be re-activated against an established tumor. However, only a minority of patients responds to the currently available ICI. New strategies to target additional pathways to reverse cancer-associated immune suppression are therefore needed.Others and my group within the Cancer Immunology Laboratory in Basel have defined a new adaptive, immunosuppressive pathway, the sialoglycan-Siglec-9 pathway that involves sialic-acid binding immunoglobulin-like lectin (Siglec) receptor 9 and upregulation of sialic acid-containing Siglec ligands (sialoglycans) in the tumor microenvironment. We have also recently described and upregulation of the inhibitory Siglec-9 receptor on tumor-infiltrating T cells.The general objective of this project is to delineate the role of Siglec receptors and Siglec ligands in adaptive anti-tumor immunity and to generate tools to target Siglec receptors and their ligands for cancer immunotherapy. First, we will elucidate Siglec signalling in tumor-infiltrating T cells. We will generate a defined Jurkat cell line overexpressing different Siglec receptor variants to elucidate their downstream signaling. To further understand signaling and pathways influenced by inhibitory Siglec receptors on tumor-infiltrating T cells, we will use these defined cell lines to perform an unbiased proteomic analysis. These findings will help to understand how Siglec-9 inhibits T cell function in cancer. Second, we will study the role of Siglecs on dendritic cells in anti-tumor immunity and also autoimmunity with new mouse models. We will perform multicolor flow cytometric analysis on non-small cell lung cancer, colorectal cancer, and epithelial ovarian cancer samples as well as tumor-draining lymph nodes to characterize Siglec expression on human dendritic cells in cancer patients. In addition, we will use genetic mouse models to study the function of Siglecs on dendritic cells in cancer and autoimmunity. Finally, in collaboration with Carolyn Bertozzi at Stanford, agents that target Siglec receptors and their ligands in cancer will be developed. Already established preclinical models will be used for combination immunotherapy regimens together with established ICI and mechanisms of anti-tumor immune activation will be studied in vivo.With the proposed research project, we will improve our understanding for the role of the Siglec-sialoglycan immunosuppressive pathway in cancer patients. We have produced a set of tools for in vitro and in vivo studies of the sialoglycan-Siglec pathway that will significantly move potential compounds further in the preclinical and hopefully into future clinical development. Our findings will be highly relevant to translate the basic scientific findings into clinically active drugs that will help cancer patients, synergize with ICI and improve current cancer immunotherapies.
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