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Decoding the Cancer Glycoproteome Driven Immune Response

Periodic Reporting for period 1 - GlyCANswer (Decoding the Cancer Glycoproteome Driven Immune Response)

Okres sprawozdawczy: 2019-05-15 do 2021-05-14

Cancer continues to be a big challenge in modern medicine and the second leading cause of deaths worldwide. However, in recent years, the treatment of unresectable cancer has undergone a paradigm shift with the advent of immunotherapy. Unfortunately, despite the great progress in the field, the majority of breast cancer patients still do not respond to any of the available immunotherapeutics and no reliable biomarker exists to predict those patients that would benefit from it. This shortcoming is due to an incomplete understanding of how cancer cells interact with the immune system. One of the cancer cell mechanisms, whose immunomodulatory function is poorly understood, is glycosylation. Glycosylation is the modification of cell products with complex carbohydrates. These carbohydrates fulfill important functions in the communication and regulation of tissue organization and in regulating the immune system. However, it is still technically difficult to assess the glycosylation of cancer cells. Therefore, this project aimed to develop a new method to analyze the cancer cell glycosylation and thus to improve our understanding how cancer cell glycosylation regulates the immune system. This would facilitate the development of new strategies for immunotherapy and identify improved predictive biomarkers for treatment response.
In this project various complementary methods for the analysis of the glycosylation of cancer cells were applied to provide a comprehensive characterization of the cancer cells. In addition, a completely new method to analyze glycoproteins produced by cancer cells was established yielding new insights into the cancer biology.
1. The glycosylation of breast cancer cells has been measured.
The glycosylation of cancer cells was analyzed using various complementary approaches such as lectin and antibody stainings which were used to quantify the specific glycan-epitopes on cancer cells. In addition, cancer cells were analyzed using state-of-the-art glycoproteomics to get a complete overview on the cancer cell glycosylation. Lastly, gene expression analysis was performed to provide an understanding of changes in the glycosylation machinery of cancer cells that led to the formation of measured glycan-epitopes and glycoproteins.

2. Mechanisms of immune regulation have been studied.
The glycosylation of cancer cells was altered through genetic and pharmacologic approaches. These cancer cells were then compared with their unaltered cancer cells on their capacity to change the anti-cancer immune response. The results provided a deeper understanding how cancer cell glycosylation controls the immune system and contributes to the aggressive progression of tumors.

3. A glycan-binding protein library has been established for an improved analysis of the glycosylation in diseases
A lectin (glycan-binding protein) library consisting of more than 130 mammalian lectins, many of which are key components of the immune system, has been produced and used to study diseases. As first proof of concept, these lectins have been used to identify new SARS-CoV-2 binding proteins. These findings have been published in a peer-reviewed open-access journal: https://doi.org/10.15252/embj.2021108375

4. New methods have been established to assess breast cancer alterations.
A new method to assess the glycoprotein produced by breast cancer cells has been rigorously established and optimized. The method allowed to assess with an unprecedented detail the analysis of cancer cell glycoproteins. This new data builds the foundation for future studies that will be published in open access papers and disseminated in the future.

No website has been developed for the project.
The data generated in this project provides an improved understanding on the alterations of glycosylation in breast cancer. It also provides new mechanistic insights in the regulation of the immune system. Although, this project is not entirely completed, it is suspected that the final publication that will follow from this project will provide a map of the cancer cell glycosylation, which other researchers can utilize as a resource, as well as a comprehensive overview of the immunoregulatory capacity of cancer cell glycosylation. Although still uncertain, this may lead to improved therapeutic options for the immunotherapy of cancer patients in the future and improve the survival of cancer patients worldwide.

Lastly, new methods that can be employed for the analysis of cancer glycosylation have been developed. These methods will be further improved and used in the future to gather unprecedentedly detailed information on the malignant process taking place in a tumor. Also this method holds promise to catalyze future ambitions to develop new treatments and identify new biomarkers for cancer and may thereby improve the outcome of cancer patients around the globe.
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