Changing the anti-tumor immune response through differentially glycosylated tumor-specific IgG

• Applicant: Dr. Jasper Prüßmann
• Subject Area: Rheumatology ; Hematology, Oncology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289291972

The role of antibodies (Ab) in the anti-tumor immune response is poorly understood. While some studies suggest a cancer-promoting effect during early tumorigenesis or in animals with established tumors, others indicate possible anti-tumor activities of tumor-specific Abs. Apart from Ab-dependent cellular cytotoxicity, the main anticipated function of Abs formed against tumor antigens (Ag) is the targeting of Ags to antigen-presenting cells (APC) in tumor tissue or in tumor-draining lymph nodes via different immunoglobulin (Ig) receptors.One factor that has been only poorly addressed so far, but may be critical in determining the role of anti-tumor Abs, is the antibody Fc fragment glycosylation (Glyco) pattern. This pattern regulates all Ig effector activities, including affinity to IgG receptors, such as classical Fc receptors and members of the C-type lectin receptor family. It has been noted that Ig Glyco patterns change between states of health and acute or chronic inflammation. The resulting changes in Ig receptor binding preference lead to different Ig-dependent, cell-mediated outcomes. While non-galactosylated IgG have a pro-inflammatory effect, galactosylated and sialylated IgG are tolerogenic.This project aims to test the hypothesis that the Glyco pattern of Abs specific for a secreted tumor Ag determines to which type of APC and with which functional outcome this Ag is directed, resulting in preferentially tolerogenic or immunogenic Ag presentation to tumor-reactive T cells. To test this hypothesis and to determine the role of Ig Fc glycosylation, I propose the following aims:1.: To characterize the isotypes and glycosylation profile of endogenous tumor Ag-specific Abs in serum and tumor tissue in spontaneous and transplantation mouse models of cancer.2.: To determine the effect of Fc glycosylation on tumor Ag-specific IgG distribution in tumor tissue, their uptake by APCs and impact on APC maturation and activation.3.: To investigate the role of Fc glycosylation in the immune-modifying effects of tumor Ag-specific IgG and its anti-tumor activity.A substantial part of aims 2 and 3 of this project is the visualization of Ab and immune cell activity by multiphoton intravital microscopy. The possibility to image the temporal and spatial distribution and interaction of differentially glycosylated anti-tumor Abs and immune cells in tumor tissues and lymph nodes under near-physiological conditions will add important information to in vitro assays and post mortem analyses.Collectively, these studies will provide a detailed analysis of the role of Ig glycosylation in the anti-tumor immune response and will visualize for the first time the IgG distribution in tumor tissue and its interaction with immune cells. Besides understanding the functions of endogenous IgG in tumor control, this will pave the way for the development of novel therapeutic strategies to exploit the potential of tumor Ag-specific Abs in cancer patients.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Thorsten Roman Mempel, Ph.D.