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295 Tumor cell- intrinsic expression of FGFR3 drives anti-PDL-1 immunotherapy resistance in a murine bladder cancer model
  1. Erica Fleming-Trujillo,
  2. Jeffrey Bloodworth,
  3. Anthony Fernald,
  4. Aubrianna Ramsland,
  5. Thomas Gajewski and
  6. Randy Sweis
  1. University of Chicago, Chicago, IL, USA


Background Immune checkpoint blockade therapy has recently shown efficacy in treating advanced urothelial bladder cancer and anti-PD-1/PD-L1 therapy is currently the standard of care. However, most patients do not respond to these drugs and resistance mechanisms remain elusive. The non-T cell-inflamed tumor microenvironment phenotype correlates with poor prognosis and immunotherapy resistance. We previously found that activating mutations in Fibroblast Growth Factor Receptor 3 (FGFR3) were exclusive to non-T cell-inflamed bladder cancers. We 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.

Methods We developed a syngeneic transplantable murine bladder cancer model 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 (FGFR3-sec), or control. Mice were injected subcutaneously into flank and size was measured every 3 days along with PD-L1 therapy (BioXcell clone 10F.9G2). Tumors, draining lymph nodes, and spleens were harvested at endpoint for flow cytometry.

Results 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. Tumors with a secreted FGFR3 receptor (FGFR3-sec) retained responsiveness to anti-PD-L1 therapy.

Conclusions In a murine bladder cancer model, FGFR3 activation led to relative T cell exclusion and resistance to immune checkpoint blockade. The mechanism of resistance was not dependent on receptor kinase activity. Further studies are ongoing to determine the biochemical mechanisms of FGFR3-mediated immunotherapy resistance in bladder cancer.

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