Abstract 1352: Transcriptional and post-translational regulation of B7-H4.

Abstract Immune tolerance mechanisms are shared between cancer and pregnancy. By cross-analyzing single-cell RNA sequencing data from multiple human cancer types and the maternal-fetal interface, we found that B7-H4 (VTCN1) is highly expressed in both cancer cells and trophoblasts. Genetic deficiency of B7-H4 led to immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 promoted breast cancer progression, accompanied by CD8+ T cell exhaustion, indicating that B7-H4 functions as an onco-fetal immune tolerance checkpoint. We found that B7-H4 expression is transcriptionally regulated by progesterone in placental and breast cancer cells. The progesterone receptor (PR) binds to the -58 kb enhancer of the B7-H4 gene and drives its transcription through the PR-P300-BRD4 axis. Pharmacologic inhibition using a PR antagonist or BRD4 degrader enhanced the efficacy of immunotherapy in a murine B7-H4+ breast cancer model. These findings establish a mechanistic and biological link between the female sex hormone progesterone and onco-fetal immune tolerance via B7-H4, highlighting the PR-P300-BRD4 axis as a targetable pathway in B7-H4+ cancers. We next investigated the post-translational regulation of B7-H4. We discovered that ZDHHC3, a zinc finger DHHC-type palmitoyltransferase, palmitoylates B7-H4 at Cys130 in breast cancer cells, preventing its lysosomal degradation and sustaining B7-H4-mediated immunosuppression. Knockdown of ZDHHC3 elicited robust anti-tumor immunity and suppressed tumor progression in murine models. Moreover, the CDK4/6 inhibitor abemaciclib activated lysosomal pathways and promoted B7-H4 degradation. Abemaciclib treatment led to T cell activation and mitigated B7-H4-mediated immune suppression in preclinical tumor models. Overall, our study delineates transcriptional and post-translational mechanisms that regulate B7-H4 expression and stability and identifies hormonal and lysosomal pathways as therapeutic strategies for targeting B7-H4+ cancers. Citation Format: Jiali Yu, Yijian Yan, Ilona Kryczek, Weiping Zou, . Transcriptional and post-translational regulation of B7-H4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1352.