Research Investigator University of Michigan, United States
Introduction/Rationale: 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.
Methods: 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.
Results: We found that progesterone induces B7-H4 expression 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.
Conclusion: 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.
