Blocking sugar modification could boost breast cancer immunotherapy success

Immunotherapies such as so-called checkpoint inhibitors activate the body's own immune system to fight cancer cells and have revolutionized the treatment of many types of tumor. In breast cancer, however, these therapies are often only of limited effectiveness. An international research team led by the Medical University of Vienna has now identified a previously underestimated mechanism by which breast tumors evade the immune system. The findings, currently published in the journal Nature Communications, also provide a new starting point for improving the effectiveness of immunotherapies in breast cancer.

Sialylation is the name given to the biochemical process that the research team led by Stefan Mereiter (Department of Obstetrics and Gynaecology, MedUni Vienna) and Josef Penninger (Clinical Institute of Laboratory Medicine, MedUni Vienna) has identified as a central mechanism of immune suppression in breast cancer. This involves a specific sugar modification on the surface of tumor cells that impairs communication between cells and the immune system.

We were able to show that around two-thirds of all breast tumors exhibit increased sialylation. In these cases, significantly fewer T-cells—i.e. immune cells that fight cancer cells—were detectable in the tumor tissue."

Stefan Mereiter, lead author

Analyses of patient cohorts comprising a total of 136 breast cancer cases confirmed this link.

Targeted inhibition of the mechanism

In detail, the researchers discovered that sialylation, among other things, enhances the effect in the blood of the immunomodulatory growth factor G-CSF produced by cancer cells. This leads to an increased recruitment of immunosuppressive cells into the tumor, which in turn prevent cytotoxic, i.e. cell-killing, T-cells from efficiently penetrating the tumor tissue. At the same time, sialylation makes tumor cells less recognisable to existing T cells, thereby allowing them to evade the immune system. In preclinical research models, however, the targeted pharmacological inhibition of sialylation led to T cells spreading throughout the tumor again and being able to combat it more effectively: "More activated cytotoxic T cells reach the tumor, whilst at the same time immunosuppressive neutrophil cells decrease," explains study leader Josef Penninger.

Breast cancer is the most common cancer in women. Immunotherapies, such as so-called checkpoint inhibitors, which are designed to activate the body's own immune system to defend against cancer cells, are only of limited effectiveness against this type of tumor. The current study results provide both a possible explanation and a solution for this: "Our study shows that therapeutically blocking sialylation causes even tumor models that were previously resistant to treatment to respond to immunotherapies. Our findings therefore suggest that the targeted modulation of tumor sialylation could be a promising new approach to overcoming immune-suppressive mechanisms within the tumor and thus significantly improving the efficacy of immunotherapies in breast cancer," said Mereiter and Penninger. The findings are now to be further investigated in additional studies within the newly established research group led by Stefan Mereiter at the Department of Obstetrics and Gynecology at MedUni Vienna, with the aim of developing future therapies.