{
  "abstract": "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 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.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.",
  "authors": [
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Mireia Cruz De los Santos"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden",
        "Division of Hematology and Oncology, Columbia University, New York, New York, USA"
      ],
      "name": "Yi Chen"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Amaia González De Zárate"
    },
    {
      "affiliations": [
        "Department of Women's, and Children's Health,Childhood Cancer Research Unit, Karolinska Institutet, Solna, Sweden"
      ],
      "name": "Agnes Sorteberg"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Honglei Zhao"
    },
    {
      "affiliations": [
        "Institute of Environmental Medicine, Toxicology Unit, Karolinska Institutet, Solna, Sweden"
      ],
      "name": "Guillermo Vázquez-Cabrera"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Neda Bigdeli"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Solrun Kolbeinsdottir"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Aarren Mannion"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Lucas Baldran-Groves"
    },
    {
      "affiliations": [
        "Singapore Immunology Network, Agency for Science, Technology and Research, A*STAR, Singapore"
      ],
      "name": "Shi Yong Neo"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Stina Linnea Wickström"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Jeroen Melief"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Lars Holmgren"
    },
    {
      "affiliations": [
        "Department of Women's, and Children's Health,Childhood Cancer Research Unit, Karolinska Institutet, Solna, Sweden",
        "Section Pediatric Oncology, Astrid Lindgren Children’s Hospital, Stockholm, Sweden"
      ],
      "name": "Nikolas Herold"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden",
        "Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden"
      ],
      "name": "Felix Haglund de Flon"
    },
    {
      "affiliations": [
        "Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Andreas Lundqvist"
    }
  ],
  "title": "Epigenetic remodeling in sarcoma promotes T-cell infiltration via modulation of the Hippo pathway",
  "uid": "f5007dd1-5652-5b00-880e-8a7cef432a9b"
}