Yung Lyou, MD from the City of Hope speaks about High-throughput global transcriptional profiling to identify the STAT3 signaling pathway as a potential biomarker for immune checkpoint inhibitor resistance in metastatic/advanced urothelial carcinoma.
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A major public health burden, with a median overall survival of 15 months, is advanced/metastatic urothelial carcinoma (UC). While an additional second-line treatment choice has been offered by immune checkpoint inhibitors (ICI), only 15-40% of patients can react. In order to further develop these therapies, there has been a great deal of work to establish the mechanisms of immunotherapy resistance and predictive biomarkers.
For study, pre-treatment genomic sequencing data derived from FFPE samples from the clinical IMVIGOR210 trial (n=298) was accessed. A single arm phase II clinical trial was briefly performed in which advanced/metastatic UC patients who were refractory to platinum chemotherapy received ICI atezolizumab. This research was published with extensive techniques (PMID: 28950298). Using standard QC steps, the raw sequencing information was pre-processed and matched to the human reference genome (hg38). To produce the gene level counts for differential gene expression, the resulting outputs were then normalized and processed (DGE). DGE research was conducted comparing atezolizumab with patients who had clinical benefit (CR, PR, SD) and non-clinical benefit (i.e. PD). The list of genes differentially expressed was then analyzed using different methods for gene ontology, pathway and systems biology (IPA, Enrichr, and X2Kweb). Using gene-gene correlations (i.e. PD-L1 and STAT3) and clinicopathologic characteristics, further subset analysis was performed (eg. gender, race, smoking history).
Of the 298 patients in this study, 25 had CR, 43 had PR, 63 had SD, and 167 had PD based on atezolizumab clinical response. Subgroup review for patients with CR vs PD showed that approximately 847 genes with statistical significance were expressed differentially (p ⁇ 0.05). 'Primary immunodeficiency' and 'sirtuin signaling' were the IPA study for this list of differentially expressed genes located in the top signaling pathways. Further subset study of 39 genes (p ≤ 0.01) enriched in PD patients using Enrichr and X2kweb showed that there was an overrepresentation of STAT3 signaling genes (hypergeometric p-val 6.32x104).
Our findings showed that there was differential gene expression in STAT3, primary immunodeficiency, and sirtuin signaling pathways when the transcriptional profiles of CR vs PD occurred. Of note, STAT3 signaling has been reported to modulate immune function and its expression is associated with poor prognosis in patients with urothelial carcinoma. These findings require a wider study to see whether a possible biomarker for ICI resistance is STAT3 signaling. This could mean that the STAT3 pathway, if validated, is a possible therapeutic target for overcoming ICI resistance and enhancing the effectiveness of these agents.