Epigenetic remodeling in sarcoma promotes T-cell infiltration via modulation of the Hippo pathway

Insufficient T-cell infiltration limits the effectiveness of immunotherapy in sarcoma, yet the tumor-intrinsic mechanisms that govern immune exclusion remain poorly defined.

By integrating patient-derived ex vivo sarcoma spheroids with autologous expanded tumor-infiltrating lymphocytes and an in vivo metastatic osteosarcoma model, antitumor immune regulation by histone modifications was examined.

Histone H3 lysine 27 acetylation (H3K27ac) was identified as a key regulator of CD8⁺ T-cell infiltration in osteosarcoma and other bone and soft-tissue sarcomas. Pharmacological elevation of H3K27ac by the histone deacetylase 1/3 inhibitor entinostat promotes CD8⁺ T-cell activation, cytotoxicity, and the recruitment of CD8⁺CD103⁺ tissue-resident memory T cells. Mechanistically, these immune-boosting effects are triggered by a Hippo pathway switch, in which yes-associated protein 1 (YAP1) is suppressed, and vestigial-like family member 3 (VGLL3) is induced, thereby modulating transcription towards an immune-responsive state. Furthermore, we identified that VGLL3/CD103 signatures predict a response to anti-programmed cell death protein-1 (PD-1) treatment in patients with sarcoma, and that combining H3K27ac induction with anti-PD-1 further augments T cell-mediated killing in ex vivo autologous patient-derived spheroid models.

Our findings reveal an epigenetic-Hippo-immunomodulatory axis in osteosarcoma that also extends to other sarcomas, providing a rationale for incorporating epigenetic preconditioning with immunotherapy to improve patient outcomes and pointing towards novel biomarkers for treatment guidance.