β-catenin inhibition using XAV939 nanoparticle promotes immunogenic cell death and suppresses tumor progression

Abstract

Abstract Although the incidence of conjunctival melanoma is rare, it is a highly metastatic tumor with high recurrence and mortality rates. The current conjunctival melanoma treatment strategies, including surgical resection combined with chemo- or cryotherapy, have limited usefulness because of systemic side effects, recurrence, and metastases. Tumor-intrinsic Wnt/β-catenin pathway mediates immune exclusion in the tumor microenvironment (TME) and promotes tumorigenesis. Previous studies have shown that XAV939, a potent tankyrase inhibitor, can be used for the pharmacological inhibition of β-catenin. In this study, using tocopheryl polyethylene glycol 1000 succinate (TPGS)-based nanoparticle formulation for XAV939, we show that β-catenin inhibition suppresses melanoma cell proliferation and migration. Additionally, XAV939 nanoparticles promoted immunogenic cell death (ICD) of tumor cells with a significant extracellular release of ICD molecules, including HMGB1, calreticulin, and ATP. Further, using a mouse model of conjunctival melanoma, we show that β-catenin inhibition significantly suppresses conjunctival melanoma progression. Collectively, the local delivery of β-catenin represents a novel and safe approach to promoting ICD and activating anti-tumor immunity for combinatorial immune checkpoint inhibition therapies against vision and life-threatening ocular melanomas. This study was supported by research funding from the Intramural Grants Program, Auburn University Research Initiative in Cancer (AURIC), and start-up funds from the Department of Pathobiology, College of Veterinary Medicine, Auburn University.