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 study, we determined tumor-oncogenic pathways correlating with T-cell exclusion. We first establish in this report 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. β-Catenin, PPAR-γ, 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. Cancer Immunol Res; 4(7); 1–6. ©2016 AACR.
Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).
Prior presentation: Presented at 51st Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 29–June 2, 2015.
- Received November 10, 2015.
- Revision received February 9, 2016.
- Accepted April 7, 2016.
- ©2016 American Association for Cancer Research.