{
  "abstract": "Background Immune-checkpoint blockade therapies have revolutionized cancer treatment; however, such immunotherapy regimens fail in a subset of patients. Developing new combination regimens to enhance immunotherapy efficacy, and identifying biomarkers to predict therapy response will facilitate optimal patient selection, and ultimately improve the long-term survival of patients.Methods We leveraged a cohort of 85 patients with advanced hepatocellular carcinoma (HCC) exhibiting varying responses to Atezolizumab plus Bevacizumab (Atezo/Bev), and profiled the tumor ecosystems using single-cell transcriptome sequencing and mass cytometry by time of flight for 10 patients. We integrated our in-house data and additional published scRNA-seq cohorts of 83 donors to generate a comprehensive landscape of cellular dynamics. Plasma protein levels were quantified both before and after treatment across all patients. The predictive and prognostic value of biomarkers were verified in our in-house tumor microarray of 342 patients.Results Tumor cell up-regulated UCHL1 to nullify anti-PD-L1 therapy by driving conventional DC transformation into mature DC enriched in immunoregulatory molecules (mregDC) and promoting mregDC and regulatory T (Treg) cell crosstalk, thereby restraining CD8 + T anti-tumor immunity. Mechanistically, UCHL1 enhances glycolysis and lactate accumulation by stabilizing HIF-1α, which in turn promotes SREBP2 activation and nuclear translocation in DC, leading to its tolerogenic maturation. We verified the positive correlations between UCHL1 and HIF-1α/VEGFα/LAMP3/FOXP3 in 342 patients with HCC. Genetic ablation or pharmacological inhibition of UCHL1 reduced mregDC and Treg accumulation, restored immune surveillance of tumor-infiltrating lymphocytes, and safeguarded anti-tumor immunity and efficacy of anti-PD-L1 therapy in mouse models. Pre-treatment plasma UCHL1 levels serve as a predictor of response to Atezo/Bev therapy in patients with HCC.Conclusions UCHL1 hijacks tolerogenic DC maturation to promote mregDC-Treg crosstalk to nullify anti-PD-L1 therapy. Genetic ablation and pharmacological inhibition of UCHL1 unleash the immune surveillance of tumor-infiltrating lymphocytes, and safeguard anti-tumor immunity. Baseline plasma UCHL1 levels effectively predict the efficacy of Atezo/Bev therapy in patients with HCC ( figure 1).Ethics Approval This study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (IRB number: B2021-464).Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 481 Figure 1UCHL1 hijacks tolerogenic dendritic cell maturation and promotes mregDC-Treg crosstalk to nullify checkpoint blockade",
  "authors": [
    {
      "affiliations": [
        "Zhongshan Hospital, Fudan University, Shanghai, China"
      ],
      "name": "Yufei Zhao"
    },
    {
      "affiliations": [
        "Zhongshan Hospital, Fudan University, Shanghai, China"
      ],
      "name": "Hui Li"
    },
    {
      "affiliations": [
        "Zhongshan Hospital, Fudan University, Shanghai, China"
      ],
      "name": "Qinghai Ye"
    }
  ],
  "title": "481 UCHL1 hijacks tolerogenic dendritic cell maturation and promotes mregDC-Treg crosstalk to nullify checkpoint blockade",
  "uid": "815c8bdc-0e36-52a6-8378-173ffabeeb4e"
}