Sialoproteome driven immune response in breast cancer

Cancer is still one of the greatest challenges in modern medicine and the second leading cause of deaths worldwide. Fortunately, new and very promising treatments are being developed, which foster the patients own immune system in combatting cancer the so-called immunotherapy. Yet, despite the great progress in treating cancer, immunotherapy does not work for the majority of breast cancer patients. In order to develop improved immunotherapies that may work in a larger number of breast cancer patients, we need to better understand how breast cancer keeps the patients immune system in check. To do so, this project will focus on an aspect of breast cancer that is still poorly understood and which has a great impact on controlling the immune system, namely glycosylation. All the cells of our body engage in glycosylation, which is the production of complex sugar molecules called glycans, to present these glycans on their cell surface. Glycans are important in defining how our bodys cells interact with each other and also important for our immune system to discern our own cells from pathogens. Cancer cells are capitalizing this system by producing altered glycans on their surface to protect them from the recognition by the immune system. As a consequence, the immune system fails to identify cancer cells as targets to be cleared. In this 3-years project funded by the FWF, I aim to improve our understanding on how breast cancer cells change their glycans. By using a newly developed technique the changes of glycosylation in breast cancer will be analyzed with unprecedented detail. In addition, I will assess how the altered glycosylation influences the immune system and if we can revert this process through medication. The final goal of this project is, to define the key processes of breast cancer glycosylation which could be targeted for next generation immunotherapies for breast cancer patients.

Breast cancer is the most common cancer among women worldwide. In recent years, new types of cancer treatments called immune checkpoint inhibitors have shown great success in fighting cancers such as melanoma and lung cancer by activating the body's own immune system. Unfortunately, these therapies have not been very effective for most breast cancer patients. Our project set out to understand why the immune system fails to effectively attack breast tumors and to identify new ways to make immunotherapy work better in this disease. Using advanced molecular analysis, we created the most detailed map to date of sugar-modified proteins (the glycoproteome) in breast cancer cells. These sugar structures, especially a type called sialic acids, turned out to play a key role in helping tumors hide from the immune system. We discovered that blocking the addition of sialic acids on tumor cells, either through genetic or drug-based approaches, can reinvigorate the immune response. This shift changes the tumor environment from one that suppresses immune activity to one that supports it, reducing harmful immune suppressive cells and increasing the number of cancer killing CD8+ T cells. At the molecular level, sialic acids were found to regulate key immune signals on tumor cells, including MHC class I and PD-L1, which are crucial for how the immune system recognizes and attacks cancer. Importantly, when we inhibited sialylation in animal models of breast cancer, tumors that were previously resistant became vulnerable to immune attack and responded much better to anti-PD-1 immunotherapy. We also confirmed that over half of human breast tumors display high levels of these sialic acid modifications, which correlate with poor immune infiltration. In summary, our findings reveal sialylation as a central mechanism by which breast tumors evade immune control. By targeting these sugar modifications, it may be possible to turn previously unresponsive breast cancers into tumors that can be effectively treated with existing immunotherapies. This work opens new avenues for improving outcomes for breast cancer patients who currently have few immunotherapy options.