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Targeting LRBA triggers CTLA4 degradation and antitumor immunity for cancer immunotherapy

ABSTRACT: The lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency causes severe autoimmune diseases and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) loss in humans. However, the impact of LRBA on antitumor immunity remains understudied. Here, we identified the role of LRBA in antitumor immunity and developed a novel immunotherapy for cancers. Interestingly, LRBA was negatively associated with antitumor immunity in human patients. Using high-throughput screening and subsequent structure-based hit optimization, we discovered a small molecule LC427 that bound directly to LRBA, and selectively interfered with the LRBA-CTLA4 interaction. This mechanistically unique LC427 facilitated the lysosomal degradation of CTLA4, and bolstered survival and functions of activated T cells. Importantly, orally administrated LC427 increased tumor-infiltrating CD8+ T cells and displayed effective antitumor activity in tumorbearing mouse models. Notably, LC427 did not induce typical irAEs observed with immune checkpoint inhibitors in colitis models. Our study demonstrates that targeting LRBA offers a novel and effective strategy with a favorable safety profile, highlighting the potential of LRBA-based immunomodulatory therapies in the treatment of cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE297744 | GEO | 2025/05/23

REPOSITORIES: GEO

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