AI Summary
This study focuses on investigating molecular features associated with resistance to pembrolizumab in BCG-unresponsive bladder cancer. By spatially profiling tumors from patients responsive or resistant to intravenous pembrolizumab treatment, the researchers identified characteristics linked to response to the treatment. They found that tumors with an inflamed PanCK+ tumor area and an infiltrated stromal segment responded better to pembrolizumab. Additionally, they discovered that non-inflamed, immune-cold tumors that do not respond to pembrolizumab may have a favorable outcome with a combination of BCG and pembrolizumab. This research highlights the potential of using transcriptomic signatures to identify tumors more likely to respond to pembrolizumab, but further studies with larger sample sizes are needed to validate these findings.
Intravenous immune checkpoint inhibition achieves a 40% 3-month response in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ. Yet, only half of the early responders will continue to be disease-free by 12 months, and resistance mechanisms are poorly defined. We performed spatial profiling of BCG-unresponsive tumors from patients responsive or resistant to intravenous pembrolizumab treatment, analyzing samples both before initiating and 3 months post-intravenous pembrolizumab treatment. We analyzed 119 regions of interest, which included 59 pairs of epithelial and adjacent stromal segments across five patients: two responders and three non-responders. We demonstrate that BCG unresponsive tumors with an inflamed PanCK+ tumor area and an infiltrated stromal segment respond better to intravenous pembrolizumab. Furthermore, using segment-specific gene signatures generated from a cohort of BCG unresponsive NMIBC treated with intravesical BCG+pembrolizumab, we find that non-inflamed, immune-cold tumors that do not respond to intravenous pembrolizumab exhibit a favorable outcome to the combined application of BCG and pembrolizumab. For the first time, we have identified molecular features of tumors associated with response and resistance to intravenous pembrolizumab in BCG unresponsive NMIBCs. Further research with more patients and alternative checkpoint inhibitors is essential to validate our findings. We anticipate that using a transcriptomics signature like the one described here can help identify tumors with a higher possibility of responding to intravenous pembrolizumab.