Understanding cancer-cell autonomous mechanisms that shape the immune microenvironment and mediate resistance to immune checkpoint blockade in bladder cancer is of paramount importance.
An important study published by Sweis et al. in Cancer Immunology Research investigated the molecular mechanisms that contribute to the lack of immunotherapy efficacy in non-T cell-inflamed bladder cancer.
The authors classified bladder cancers into T cell inflamed, intermediate, and non-T cell inflamed groups based on a signature of 725 genes containing 12 genes from the T cell signatures. They validated the performance of these signatures by immunohistochemistry for CD8 on a subset of samples.
The investigators identified CD8+ T-cell expression and immune-inhibitory markers (IDO, FOXP3, TIM3, and LAG3) in the T-cell-inflamed bladder tumors. FGFR3 mutations and activated β-catenin, PPAR-γ regulators, were enriched in the T cell non-inflamed group. There was no significant difference in the number of nonsynonymous mutations per patient for each group mutations between the T cell-inflamed and non-T cell-inflamed subtypes.
This study confirms previous observations and provides critical insights into the cancer signaling pathways that shape the immune microenvironment of bladder cancer. Targeting these pathways can potentially increase the response of T cell ‘cold’ tumors to immunotherapy.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York
- 1. Sweis, R. F., S. Spranger, R. Bao, G. P. Paner, W. M. Stadler, G. Steinberg, and T. F. Gajewski. "Molecular drivers of the non-t-cell-inflamed tumor microenvironment in urothelial bladder cancer." Cancer Immunol Res 4 (7): 563–568. doi: 10.1158/2326-6066. CIR-15-0274, 2016.