Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer

Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what controls the spatial distribution of T cells in the tumour microenvironment is not well understood. Here we couple digital pathology and transcriptome analysis on a large ovarian tumour cohort and develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGF beta and activated stroma. Furthermore, we identify TGF beta as an important mediator of T cell exclusion. TGF beta reduces MHC-I expression in ovarian cancer cells in vitro. TGF beta also activates fibroblasts and induces extracellular matrix production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGF beta might be a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy. The exclusion of T cells from solid tumours is a potentially important mechanism that regulates whether or not cancer patients respond well to checkpoint blocking immunotherapies. Here the authors identify immune phenotypes and mediators of T cell exclusion among ovarian cancer patient samples from the ICON7 phase III trial.