The tumour-associated Tn antigen fosters lung metastasis and recruitment of regulatory T cells in triple negative breast cancer

Abstract

Abstract Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths. Among breast cancers (BC) subtypes, triple-negative (TN) BC, is characterized by metastatic progression and poor patient prognosis. Although, TNBC is initially sensitive to chemotherapy, many TNBC patients rapidly develop resistance, at which point metastatic disease is highly lethal. Cancer cells present phenotypic changes or molecular signatures that distinguish them from healthy cells. The Tn antigen (GalNAc-O-Thr/Ser), that constitutes a powerful tool as tumour marker, was recently reported to contribute to tumour growth. However, its role in BC-derived metastasis has not yet been addressed. In this work we generated a pre-clinical orthotopic Tn+ model of metastatic TNBC, that mimics the patient surgical treatment and is useful to study the role of Tn in metastasis and immunoregulation. We obtained two different cell clones which differed in their Tn antigen expression: a high Tn-expressing and a non-expressing clone. Interestingly, the Tn-positive cell line generated significantly larger tumours and higher degree of lung metastases associated with a lower survival rate than the Tn-negative and parental cell line. Furthermore, we also found that both tumours and draining-lymph nodes from Tn+-tumour bearing mice presented a higher frequency of CD4+ FoxP3+ T cells, while their splenocytes expressed higher levels of IL-10. In conclusion, this work suggests that the Tn antigen participates in breast tumour growth and spreading, favouring metastases to the lungs that are associated to an immunoregulatory state, suggesting that Tn-based immunotherapy could be a strategy of choice to treat these tumours.