Pilot: Hivep2 Links Glucose Metabolism and Tumor Immune Evasion

Project Summary The advent of immune checkpoint inhibitor (ICI) therapy has revolutionized the management of metastatic triple-negative breast cancer (TNBC). However, despite its advancements, complete and durable remissions remain rare. It is imperative to comprehend the molecular mechanisms driving immune evasion in TNBC for overcoming these challenges and extending patient survival. Our study reveals that Hivep2, a large zinc finger protein, is associated with poor prognosis in breast cancer. Notably, we demonstrate that elevated levels of glucose and glutamine promote Hivep2 proteolytic cleavage, leading to increased mature Hivep2 levels. Strikingly, our observations indicate that only mature Hivep2, as opposed to mRNA or precursor forms, is significantly elevated in TNBC cell lines. Moreover, we found that knockdown of Hivep2 down- regulates the expression of PD-L1. In this application, we propose to elucidate how metabolic reprogramming regulates the maturation of Hivep2 and investigate how Hivep2 induces tumor immune evasion, along with the underlying mechanisms of dysfunction imprinting. Our proposal is innovative and significant as Hivep2 functions as a master transcriptional factor that enhances the expression of PD-L1, thereby promoting TNBC tumor immune evasion. We will use imaging core. The support from this pilot study will enable us to gather more preliminary data for R01 grant applications.