Investigating the role of Periostin in chemotherapy resistance via macrophage recruitment in TNBC

Triple negative breast cancer (TNBC) accounts for 15-20% of incident breast cancers. The standard-of-care for this type of cancer is chemotherapy. However, the aggressive behaviour of TNBC often leads to chemotherapy resistance as well as a high rate of metastatic relapses. Periostin (POSTN) is an extracellular matrix protein, highly expressed in breast cancer and correlates with poor prognosis. We have recently shown that POSTN mediates resistance to anti-angiogenic therapy via macrophage recruitment in pancreatic neuroendocrine tumours. Notably, its deletion dampens monocyte/macrophage recruitment and enhances cytotoxic CD8+ T-cell infiltration. A most recent finding reveals that tumour-associated macrophages are implicated in immune-checkpoint blockade (ICB) resistance by supporting PD1+ regulatory T cells, which sequester the PD1 antibody. These findings may thus support our hypothesis that chemotherapy may fail to produce tangible responses in TNBC because of its ability to trigger stromal POSTN production, leading to the recruitment of pro-tumoural macrophages, which in turn facilitate tumour growth. Building on this work we will investigate POSTN-mediated macrophage immunity and the resulting effect on T-cell immunity. Here, I show that chemotherapy induces POSTN production in primary tumours of syngeneic mouse models of TNBC and it is particularly deposited at the invasive front. Moreover, in 2D, chemotherapy increases POSTN expression when human cancer cells and fibroblast are in direct contact. I am currently optimising two 3D models: a semi-high throughput decellularised tissue model of primary TNBC, and tri-culture in collagen gels, to functionally and mechanistically characterize POSTN regulation during chemotherapy/ICB therapy, and study polarization and recruitment of pro-inflammatory monocytes. Overall, understanding the nature of chemotherapy resistance in TNBC can be beneficial in the future for the development of therapies to treat this aggressive type of cancer.