Mentor Name: Bangxing Hong

Despite the development of novel therapeutics for pediatric brain tumors, therapy resistance remains a significant challenge that compromises patient survival. Bruton’s tyrosine kinase (BTK), a non-receptor kinase, plays a crucial role in immune signaling activation through B cell receptor (BCR), Toll-like receptor (TLR), and chemokine signaling pathways. Using both in vitro and in vivo models of human and murine pediatric glioma model, we have confirmed that BTK is not only highly expressed in tumor-infiltrating B cells and myeloid cells but is also upregulated by indoximod (IDO inhibitor)-virotherapy through a feedback mechanism. Targeting BTK not only promotes the formation of tertiary lymphoid structures (TLS) but also reverses the IDO-mediated-immunosuppression. Collectively, our findings suggest that BTK inhibition represents a novel and effective strategy to augment the anti-tumor efficacy of indoximod-virotherapy. This proposal aims to further investigate and define the underlying mechanisms by which BTK inhibition overcomes indoximod-virotherapy resistance and induces anti-tumor immunity. Aim 1: To investigate the role of BTK in tumor-infiltrating myeloid and B cells during indoximod-virotherapy of pediatric glioma. We will use both human and murine pediatric glioma models to define the immune and non-immune roles of BTK signaling in tumor-infiltrating myeloid cells and B cells. Aim 2: To evaluate the effects of BTK inhibition on tumor-infiltrating brain cells and immune cells during indoximod treatment of pediatric glioma. We will assess the anti-tumor efficacy and underlying mechanisms of combining BTK inhibitors with immunotherapy in pediatric glioma models.