Effect of low FGFR3 but high CD8 T cell infiltrated immune micro-environment on treatment response with pembrolizumab in upper tract urothelial carcinoma.

Abstract

69 Background: Although several evidence revealed that upper tract urothelial carcinoma (UTUC) with fibroblast growth factor receptor 3 (FGFR3) mutations and/or expressions follow favorable outcomes, the relationship between immune cell markers and FGFR3 expression remains unknown. We aimed to clarify FGFR3 based immune microenvironment and to investigate biomarkers to predict treatment response of Pembrolizumab (Pem) in UTUC patients. Methods: We conducted immunohistochemical (IHC) staining of 214 UTUC patients. FGFR3, CD4, CD8, CD68, CD163, CD204, and PDL-1 expressions were examined and we created immune clusters assessed with heatmap clustering. We assessed the relationships of these immune markers toward further prognosis. In addition, neutrophil-lymphocyte ratio (NLR) and absolute monocyte count (AMC) were evaluated as blodd markers for predicting treatment response from Pem. Results: Among the UTUC patients, 109 (50.9%) showed high FGFR3 expression, and showed favorable prognosis compared to the counterparts. Among the six immune markers, CD8 high expression was revealed as an independent favorable factor (HR=0.44) whereas CD204 high was shown as one of independent prognostic factors for cancer death (HR=1.80). From the FGFFR3 based immune clustering, three immune clusters were identified in UTUC tumor specimen. Cluster A showed FGFR3 low with TAM rich component (CD163 and CD204 high) followed with poor prognosis due to poor response to Pem. Cluster B showed FGFR3 low with immune hot component (CD8 high) followed with most favorable prognosis due to good response to Pembrolizumab. Cluster C showed high FGFR3 expression but immune cold component, followed with favorable prognosis due to FGFR3 high expression but poor response was confirmed with Pem. Regarding of blood biomarkers, NLR showed correlation with CD8 expressions while AMC showed correlation with CD204 expressions. By using validation cohort (n=138), NLR<3.3 showed significantly longer survival compared to the counterparts with Pem treatment (p=0.046). Conclusions: The present study demonstrated a unique immune profile found in UTUC patients. Although most of the patients show poor response to Pem, low FGFR3 expression with immune-hot status may receive clinical benefit from Pem treatment.