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

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.

MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response

“…Tn antigens and shorter linear mucin-type O-glycan core structures, typically found on cancer cells in patients with poor prognosis, 54,55 were better recognized by all sera compared to the peptides with extensive glycosylation with branched core 2 and core 4 structures, typically found on healthy cells. These latter diminished antibody recognitions of all antisera (Figure 8), suggesting that vaccine conjugates preferentially induced a tumor-specific humoral immune response.…”

Diagnostic value of double low-dose targeted perfusion CT imaging for the diagnosis of invasive and preinvasive pulmonary ground-glass nodules: systematic review and meta-analysis

“…Early preinvasive and invasive pulmonary GGNs are adenocarcinomas that are smaller than 3 cm in diameter, with pathological types have conducted extensive research on intrapulmonary GGNs. However, the focus of each study is different, the inclusion criteria for GGNs and the grouping criteria for lesion types are not consistent, the evaluation of nodule imaging signs is subjective Therefore, the objective of this study was to systematically evaluate the quality of previous studies and to analyze the diagnostic value of the size, density, vacuole, burr, lobular, and pleural depression signs in early preinvasive and invasive intrapulmonary GGNs in high quality literature (25). Some studies have investigated other observational indicators, such as lesion volume, quality, and relationship with blood vessels or bronchi, etc.…”

Advances in the Immunomodulatory Properties of Glycoantigens in Cancer

“…Indeed Tn + colorectal gliomas infiltrated with MGL + TAMs are characterised by an enhanced accumulation of MDSCs and reduced levels of cytotoxic CD8 + T cells [207]. In addition, our group has recently demonstrated that both lung and breast tumours expressing the Tn antigen contribute to immune evasion by inducing the recruitment of MGL + cells that produce IL-10 and favour the differentiation of tumour-infiltrating Tregs [124,208]. Interestingly, Tn + lung tumour cells also contribute to tumour angiogenesis.…”