The researchers collected normal urothelium from six donors and reported high expression of IFN receptor genes in these samples. Upon incubating samples with IFNγ for seven days, 107 genes exhibited a significant upregulation of at least twofold. Among these, there was a major shift in chemokine and cytokine genes needed for immune cell recruitment. IFNγ also stimulated the expression of human leukocyte antigen (HLA) genes. PD-L1 expression increased by approximately 5-fold. The immunoinhibitory B7 family member VSIR (VISTA) was constitutively expressed and further upregulated by IFNγ.
Next, Baker et al. examined the IFNγ transcriptomic signature in non-muscle invasive bladder cancers clustering them into those with high versus low IFN signature. Tumor recurrence was 50% more likely in patients with a low IFNγ signature score. TCGA muscle-invasive bladder tumors that lacked the IFNγ signature genes were more likely to be classified as luminal papillary and lymphocyte-negative. Survival was significantly lower among patients with basal/squamous tumors and a low IFNγ signature. Basal/squamous tumors with high IFNγ signatures exhibited significantly higher mutational signatures associated with APOBEC3 cytidine deaminases. In line with this, there was a significant correlation between IFNγ signature and neoantigen load.
The findings from this study are valuable as they enhance understanding of signaling pathways required for immune system activation in the context of tumor surveillance, showing that both normal urothelium and bladder cancer present a locally immunosuppressive environment, with induction of PD-L1 by IFNγ acting as a negative feedback loop. This is particularly important for adjusting immunotherapy protocols to boost efficacy. MIBC tumors with high IFN signatures may be more responsive to immune checkpoint blockade treatment. For NMIBC, researchers suggest that BCG treatment, combined with blocking VISTA and PD-L1, would potentially increase the efficacy of BCG.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
References:
- Baker SC, Mason AS, Slip RG, et al. The Urothelial Transcriptomic Response to Interferon Gamma: Implications for Bladder Cancer Prognosis and Immunotherapy. Cancers (Basel). 2022;14(21):5295. Published 2022 Oct 27. doi:10.3390/cancers14215295