Stefan Mereiter

Austria

Tumor sialylation controls effective anti-cancer immunity in breast cancer

Stefan Mereiter1,2, Gustav Jonsson1,2, Tiago Oliveira1,2, Josef M. Penninger1,2,3,4

1. Eric Kandel Institute, Department of Laboratory Medicine, Medical University of Vienna, Spitalgasse 23, Vienna, Austria
2. Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Dr. Bohr-Gasse 3, Vienna, Austria
3. Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver Campus, 2350 Health Sciences Mall, Vancouver, BC, Canada
4. Helmholtz Centre for Infection Research, Braunschweig, Germany

Abstract

Background

Breast cancer is the most common cancer among women. However, immune checkpoint inhibitors, which have revolutionized treatment across multiple cancers, remain largely ineffective in most breast cancer patients, highlighting the need for novel therapeutic strategies.

Methods

To uncover new immune-evasive mechanisms in breast cancer, we generated the most comprehensive glycoproteome map of breast tumor cells, focusing on the role of sialic acid modifications. Using multiple preclinical models, we employed both genetic and pharmacologic inhibition of sialylation to assess its impact on the tumor microenvironment and anti-tumor immunity. Furthermore, we validated our findings in clinical breast cancer samples to ensure translational relevance.

Results

Disrupting sialylation rewired the tumor microenvironment, significantly reducing myeloid-derived suppressor cells while boosting Tcf7+ memory and CD8+ effector T cells. Mechanistically, sialylation controlled the surface expression of MHC class I and PD-1 ligand on tumor cells, directly influencing immune recognition. Functionally, in vivo interference with sialylation empowered CD8+ T cells to mount a robust anti-tumor response, effectively eliminating breast tumors. Importantly, across multiple immunotherapy-resistant breast tumor models, the loss of sialylation rendered tumors susceptible to anti-PD-1 immune checkpoint therapy. Additionally, we found that hyper-sialylation occurred in over half of human breast cancers tested and correlated with poor T cell infiltration.

Conclusions

Our findings position sialylation as a key immunoregulator in breast cancer, orchestrating multiple pathways of immune escape. Targeting tumor sialylation not only converts immunologically inert tumors into those vulnerable to immune attack but also sensitizes them to immune checkpoint blockade, opening new avenues for more effective breast cancer immunotherapy.