Abstract 1394 USP10 stabilizes B7-H4 and promotes tumor immune evasion in breast cancer

Immunotherapy has revolutionized cancer treatment, yet its efficacy remains suboptimal in 'immune cold' tumors like triple-negative breast cancer (TNBC). Multiomic analyses and experimental validation identified the USP10-B7-H4 proteolytic axis as a promising target in treating immune-cold TNBC. Mechanistically, ubiquitylation of B7-H4 by an E3 ligase autocrine motility factor receptor (AMFR) is antagonized by deubiquitinase ubiquitin-specific peptidase 10 (USP10), leading to B7-H4 stabilization that inhibits tumor immune responses. Disruption of USP10 destabilizes B7-H4 and, in turn, enhances CD8+ T cell proliferation and pro-inflammatory cytokine release, resulting in increased antitumor immunity and inhibited tumor proliferation. In preclinical models of TNBC, breast cancer cells harboring mutant USP10 with disrupted proteolytic interaction between B7H4, leading to reinvigoration of cytotoxic CD8+ T cell activities and slowed tumor promotion. Collectively, the modulation of B7-H4 stability through the manipulation of USP10 activity presents a promising avenue for targeted approaches to overcome immune suppression and augment immunotherapy in breast cancer.