Characterize the Role and Regulation of Hivep2 in Tumor Immune Evasion

The advent of immune checkpoint blockade (ICB) therapy has revolutionized the management of metastatic triple-negative breast cancer (TNBC). However, despite these breakthroughs, complete and durable remissions remain uncommon. Understanding the molecular mechanisms behind immune evasion in TNBC is critical to overcoming these barriers and improving patient outcomes. Our study identifies Hivep2, a large zinc finger protein, as a key driver in TNBC invasion. Our finding show that Hivep2 knockdown reduces the expression of Interleukin-four induced gene 1(IL4I) and programmed cell death ligand 1 (PD-L1), leading to increased CD8+ T cell infiltration and a decreased population of regulatory T cells (Tregs). Notably, we demonstrate that elevated glucose and glutamine levels promote the proteolytic cleavage of Hivep2, resulting in increased levels of its mature form. Importantly, our data show that mature Hivep2, rather than its mRNA or precursor forms, is significantly elevated in TNBC cell lines. This mature Hivep2 positively correlates with both metastatic potential and the expression of IL4I1 and PD-L1. In this proposal, we aim to elucidate how metabolic reprogramming influences Hivep2 maturation and to investigate the mechanisms by which Hivep2 drives immune evasion. To accomplish this, we will employ a combination of biochemical analyses, clinically relevant genetic cancer mouse models, and transcriptomic approaches. This research is both innovative and significant, positioning Hivep2 as a master transcriptional regulator that enhances the expression of IL4I1 and PD-L1, thereby facilitating immune evasion in TNBC tumors.