{
  "abstract": "Background The hyporesponsiveness of tumor-infiltrating exhausted CD8 + T cells to tumor cells contributes to immune escape of renal cell carcinoma (RCC), representing a major challenge in current immunotherapy. However, the underlying molecular mechanism of CD8+ T-cell exhaustion in the tumor microenvironment remains largely unknown.Methods We first examined myocardial infarction associated transcript (MIAT) expression in RCC cell lines and clinical specimens, and analyzed its correlation with CD8 + T-cell exhaustion markers. To investigate the immunoregulatory role of MIAT, we evaluated its effects on CD8+ T-cell function using T-cell co-culture systems and humanized-peripheral blood mononuclear cells RCC patient-derived xenograft models. To determine the direct effects of MIAT on tumor cells, we assessed RCC cell malignant phenotypes following MIAT knockdown both in vitro and in immunodeficient nude mouse orthotopic xenograft models. Mechanistically, we employed RNA fluorescence in situ hybridization, chromatin isolation by RNA purification followed by mass spectrometry, RNA immunoprecipitation, and chromatin immunoprecipitation assays to identify the molecular interactions between MIAT, transcription factors, and target genes.Results MIAT was highly expressed in RCC cells and positively correlated with CD8 + T-cell exhaustion status. MIAT knockdown significantly enhanced CD8+ T-cell function with increased perforin and interferon-γ production, while reducing the expression of exhaustion markers programmed cell death protein 1 and T-cell immunoreceptor with Ig and ITIM domains. Mechanistically, MIAT was predominantly localized in the nucleus and formed a trimeric complex with transcription factor ETS proto-oncogene 1 (ETS1) and janus kinase 3 (JAK3) promoter, thereby upregulating JAK3 expression and activating the JAK3/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Importantly, ectopic expression of JAK3 largely abolished both the tumor-suppressive effects and enhanced T-cell function induced by MIAT depletion.Conclusions Our study demonstrates that the MIAT/JAK3/STAT3 pathway plays a critical role in malignant progression and immune escape of RCC through regulating CD8 + T-cell exhaustion, suggesting its potential as a therapeutic target for RCC immunotherapy.",
  "authors": [
    {
      "affiliations": [
        "Department of Urology, China-Japan Friendship Hospital, Beijing, China"
      ],
      "name": "Ming-xiao Zhang"
    },
    {
      "affiliations": [
        "Breast Department, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Academy of Medical Sciences, Guangzhou, China"
      ],
      "name": "Lan-yu Jing"
    },
    {
      "affiliations": [
        "Department of Urology, China-Japan Friendship Hospital, Beijing, China",
        "Department of Urology, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"
      ],
      "name": "Hao-tian Tan"
    },
    {
      "affiliations": [
        "Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Zi-ran Dai"
    },
    {
      "affiliations": [
        "Department of Urology, Ji'an Center People's Hospital, Ji'an, China"
      ],
      "name": "Da-zhi Long"
    },
    {
      "affiliations": [
        "Department of Andrology and Urology, Sir Run Run Shaw Hospital, affiliated with the Zhejiang University School of Medicine, Hangzhou, China"
      ],
      "name": "Han-chao Liu"
    },
    {
      "affiliations": [
        "Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "An-ze Yu"
    },
    {
      "affiliations": [
        "Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China"
      ],
      "name": "Bin Wang"
    },
    {
      "affiliations": [
        "Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"
      ],
      "name": "Zi-yin Chen"
    },
    {
      "affiliations": [
        "Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Jun-hang Luo"
    },
    {
      "affiliations": [
        "Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Zhen-hua Chen"
    },
    {
      "affiliations": [
        "Department of Urology, China-Japan Friendship Hospital, Beijing, China"
      ],
      "name": "Jian-feng Wang"
    }
  ],
  "title": "MIAT promotes tumor-infiltrating CD8+ T-cell exhaustion and malignant progression of renal cell carcinoma via activating JAK3/STAT3 pathway",
  "uid": "c2fb67de-a7d2-569b-af2f-d5805dbaf637"
}