Muscle-invasive urothelial bladder cancer is a common malignancy with poor outcomes for which immune checkpoint blockade is now showing promise. Despite clinical activity of PD-1/PD-L1-targeted therapy in this disease, most patients do not benefit and resistance mechanisms remain unknown. The non-T cell-inflamed tumor microenvironment correlates with poor prognosis and resistance to immunotherapies. In this report, we determined tumor-oncogenic pathways correlating with T cell exclusion. We first establish that T-cell-inflamed bladder tumors can be identified by immune gene expression profiling with concordance with CD8+ T cell infiltration. Upregulation of genes encoding immune checkpoint proteins PD-L1, IDO, FOXP3, TIM3, and LAG3 was associated with T-cell-inflamed tumors, suggesting potential for sensitivity to checkpoint blockade. beta-catenin, PPAR-gamma, and FGFR3 pathways were activated in non-T cell-inflamed tumors. No difference was seen in overall somatic mutational density between groups. The three pathways identified represent targetable potential pathways of tumor-intrinsic immunotherapy resistance.
- Received November 10, 2015.
- Revision received February 9, 2016.
- Accepted April 7, 2016.
- Copyright ©2016, American Association for Cancer Research.