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

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