The anti-tumoral effect of verteporfin via modulation of immune response and cancer stemness in a murine cholangiocarcinoma model

Authors

• XK Wang
• SR Malki
• B Bennett
• G Hu

Abstract

Cholangiocarcinoma (CCA) is a heterogenous malignancy derived from the epithelium in the biliary tree system with poor prognosis. Yes-associated protein (YAP) pathway was reported to affect various aspects of tumorigenesis and higher expression of YAP is negatively associated with the survival rate in CCA patients. Moreover, overexpression of YAP along with AKT in mice triggers CCA formation, suggesting YAP pathway is a potential target to control CCA. Verteporfin was reported as inhibitory effect of overgrowth of the liver induced by overexpression of YAP with cancer stemness markers. Thus, we investigated the antitumoral effect of verteporfin, a YAP inhibitor, in the YAP/AKT hydrodynamic tail vein injected murine model. The results demonstrated reduced liver weight and tumor formation in the verteporfin treated group compared to the vehicle treated group. Immune cell profiling using flow cytometry indicated verteporfin induced higher ratio of tumor-associated macrophage (TAM) M1/M2, indicating verteporfin treatment induced M2 to M1 phenotype transition. The percentage of activated CD8 T cell population was also induced by the verteporfin treatment, suggesting T cell activation might be the mechanism of verteporfin suppresses tumor progression. PD-1+CD39+CD8+ T cells were significantly reduced in the verteporfin treated group, indicating verteporfin may inhibit complete/terminal exhaustion of CD8 T cells. Single cell RNA sequence analysis showed that TAM M1 populations increased following verteporfin treatment. The verteporfin treated group decreased proportions of stemness-related expressing cells among malignant cell populations. In summary, verteporfin reduces tumorigenesis in CCA by modulation of immune cells, including anti-tumoral TAM M1, T cell activation and stemness.

Scientific Focus Area: Cancer Biology

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