{
  "abstract": "Background Osteosarcoma patients with high propensity for metastasis and recurrence generally encounter a poor prognosis. Despite the extensive exploration of immunotherapy, particularly the anti-programmed cell death protein 1 (anti-PD-1) antibody, in clinical trials, the efficacy remains unsatisfactory. A more profound comprehension of the resistance mechanisms and the development of innovative therapeutic strategies is imperative.Methods A screening was performed for drugs capable of upregulating major histocompatibility class I (MHC I) expression among clinically common drugs. The effects of the drug on both T cells and tumor cells, as well as its combination efficacy with anti-PD-1 antibody, were studied in vitro and in vivo osteosarcoma models. The molecular mechanisms underlying these biological processes were explored via RNA sequencing analysis.Results Etoposide was shown to upregulate the MHC I expression in osteosarcoma cells, thereby enhancing the cytotoxicity of CD8 + T cells. Interleukin-33 (IL-33) played a dominant role in etoposide-activated anti-tumor immune response. Etoposide promoted the secretion of IL-33 and augmented the expression of IL-33 binding suppression of tumorigenicity 2 (ST2) receptor, which activated the nuclear factor kappa-B signaling pathway and resulted in MHC I upregulation. Furthermore, etoposide was demonstrated to improve the therapeutic efficacy of anti-PD-1 antibody.Conclusions This study revealed the molecular mechanism underlying etoposide-activated CD8 + T cell anti-tumor immunity. The combination of Etoposide and anti-PD-1 antibody has the potential to benefit patients with advanced osteosarcoma.",
  "authors": [
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Xin He"
    },
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China"
      ],
      "name": "Hanjun Li"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Haoyu Wang"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Dongqing Zuo"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Haoru Dong"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Haoran Mu"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Binghui Yang"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Yining Tao"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Xiyu Yang"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Bowen Zhao"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Tao Zhang"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Yafei Jiang"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Zhuoying Wang"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Hongsheng Wang"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Liu Yang"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Yingqi Hua"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Zhengdong Cai"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Chongren Wang"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Mengxiong Sun"
    },
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China"
      ],
      "name": "Jun Gui"
    },
    {
      "affiliations": [
        "Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China",
        "Shanghai Bone Tumor Institution, Shanghai, Shanghai, China"
      ],
      "name": "Wei Sun"
    }
  ],
  "title": "Etoposide activates CD8+ T cell anti-tumor immunity in osteosarcoma through MHC I upregulation via tumor-secreted IL-33 mediated signaling",
  "uid": "48c92ff3-4423-5e4f-8118-73868002a95b"
}