Targeting extracellular matrix deposition from tumour cells reactivates T cell infiltration and anti-PD1 response in immune-excluded triple-negative breast cancer

A growing body of evidence supports that targeting the tumour extracellular matrix (ECM) in solid cancers holds great promises to reactivate T cell migration in immune-excluded patients. By matrisome profiling of triple-negative breast cancer (TNBC) patients, we identified two core ECM proteins enriched in fibrotic immune-excluded tumours and associated with reduced CD8+ T cell stromal infiltration, versican (VCAN) and fibronectin (FN1). Both cancer-associated fibroblasts and aggressive cancer cell lines were found to deposit these two proteins in vitro, conferring resistance to T-cell-mediating cytotoxicity. Characterisation of in vivo murine breast cancer models 4T1 and EMT6 revealed significant differences in tumour ECM deposition and immune cell composition. Accordingly, targeting Fn1 and Vcan in both models induced opposite effects on tumour growth. While it appeared unfavourable in inflamed non fibrotic tumours, deletion of Fn1 in cancer cells was beneficial in immune-excluded tumours by promoting TCF7+ T cells and restoring anti-PD1 response.