Immune evasion and immunotherapy resistance via TGF-beta activation of extracellular matrix genes in cancer associated fibroblasts

The ability to disseminate, invade and successfully colonise other tissues is a critical hallmark of cancer that involves remodelling of the extracellular matrix (ECM) laid down by fibroblasts 1 . Moreover, Cancer-Associated-Fibroblasts (CAFs) produce key growth factors and cytokines as components of the ECM that fuel tumour growth, metastasis and chemoresistance, and immune response 2-4 . ECM changes also predict prognosis in pancreatic 5 and colorectal cancers 6,7 . Here, we examine the landscape of ECM-gene dysregulation pan-cancer and find that a subset of ECM genes is ( i ) dysregulated specifically in cancer, ( ii ) adversely prognostic, ( iii ) linked to TGF-beta signalling and transcription in Cancer-Associated-Fibroblasts, ( iv ) enriched in immunologically active cancers, and ( v ) predicts responses to Immune checkpoint blockade better than mutation burden, cytolytic activity, or an interferon signature, thus identifying a novel mechanism of immune evasion for patient stratification in precision immunotherapy and pharmacological modulation.