(UroToday.com) Immune checkpoint blockade has recently shown efficacy in treating advanced urothelial bladder cancer. However, most patients do not respond to these drugs and resistance mechanisms remain undefined. The non-T cell-inflamed tumor microenvironment phenotype correlates with poor prognosis and immunotherapy resistance.
The investigators have previously found that activating mutations in Fibroblast Growth Factor Receptor 3 (FGFR3) were exclusive to non-T cell inflamed bladder cancers, and thus investigated the impact of tumor cell-intrinsic FGFR3 activation on T cell infiltration and tumor responsiveness to anti-PD-1/PD-L1 in a murine model.
A syngeneic transplantable murine bladder cancer model was developed using the MB49 cell line engineered to express FGFR3 with either the activating G370C mutation (FGFR3-G370C), a kinase-dead mutation K508M (FGFR3-K508M), a truncating mutation resulting in a secreted receptor (FGFR3sec), or control. The tumors were implanted into the flank subcutaneously and size was measured every 3 days along with PD-L1 therapy (BioXcell clone 10F.9G2). Tumors from mice inoculated with MB49-FGFR3-G370C cells showed diminished CD8+ T cell accumulation within the tumor and were resistant to anti-PD-L1 checkpoint blockade compared to MB49 controls.
To determine if FGFR3-mediated immune resistance was dependent on FGFR3 kinase activity, MB49-FGFR3-K508M tumors were evaluated and unexpectedly found to be resistant to anti-PD-L1 treatment. In contrast, tumors with a secreted FGFR3 receptor (FGFR3sec) retained responsiveness to anti-PD-L1 therapy.
Presented by: Randy Sweis, MD, University of Chicago
Written by: Roger Li, Urologic Oncologist, Moffitt Cancer Center, during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain