{
  "abstract": "Background Combination immunotherapies such as atezolizumab plus bevacizumab (Atez/Bev) and durvalumab plus tremelimumab (Dur/Tre) improve outcomes in advanced hepatocellular carcinoma (HCC), yet systemic immune mechanisms underlying response remain incompletely defined.Methods We performed single-cell RNA sequencing with CITE-seq on peripheral blood mononuclear cells from 19 advanced HCC patients (Atez/Bev: 5 responders (R), 5 non-responders (NR); Dur/Tre: 4 R, 5 NR) before and during treatment, yielding 345 962 single-cell transcriptomes spanning 22 immune cell clusters. Analysis included transcriptional profiling, gene set enrichment analysis, T cell receptor (TCR) repertoire analysis, and CellChat-based intercellular communication modeling.Results Baseline comparisons revealed distinct systemic immune states by etiology: non-viral HCC exhibited CD8 + T cells with heightened cytotoxic and memory-associated signatures. Under Atez/Bev, CD14+ monocytes in responders were reprogrammed toward antigen-presenting and lymphocyte-supporting functions, while PRKCH+ NK cells acquired a robust cytotoxic program reinforced by monocyte–NK interactions via ICAM–integrin and HLA-E–NKG2C axes. In contrast, Dur/Tre responders exhibited CD14+ monocyte programs enriched in inflammatory and interferon-driven antigen presentation, alongside transcriptional reprogramming of CD8+ central memory T cells into an effector-ready state with strong crosstalk to monocytes. TCR analysis revealed regimen-specific differences: clonotype expansion occurred irrespective of response under Atez/Bev, whereas Dur/Tre responders showed both clonotype expansion and higher pretreatment CD8+ T cell diversity, with expanded clones displaying cytotoxic and interferon-responsive profiles. Pretreatment immune composition, including naïve CD4+ T cells and PRKCH+ NK cells for Atez/Bev and conventional dendritic cells for Dur/Tre, also predicted response.Conclusions Our findings reveal regimen-specific systemic immune mechanisms in advanced HCC: Atez/Bev amplifies monocyte–NK cytotoxic axes, whereas Dur/Tre enhances monocyte–T cell inflammatory networks and TCR repertoire diversity. These insights highlight distinct predictive biomarkers and support regimen-tailored immunotherapy in HCC.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan",
        "Department of Gastroenterology and Hepatology, Japan Community Health Care Organization Osaka Hospital, Osaka, Japan"
      ],
      "name": "Akira Nishio"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan"
      ],
      "name": "Takahiro Kodama"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan"
      ],
      "name": "Kazuma Daiku"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan"
      ],
      "name": "Kazuki Maesaka"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan"
      ],
      "name": "Satoshi Tanaka"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Kansai Rosai Hospital, Amagasaki, Japan"
      ],
      "name": "Yasutoshi Nozaki"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Osaka Rosai Hospital, Sakai, Japan"
      ],
      "name": "Tomohide Kurahashi"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Toyonaka Municipal Hospital, Toyonaka, Japan"
      ],
      "name": "Kengo Matsumoto"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Higashiosaka City Medical Center, Higashiosaka, Japan"
      ],
      "name": "Takatoshi Nawa"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Osaka General Medical Center, Osaka, Japan"
      ],
      "name": "Seiichi Tawara"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Japan Community Health Care Organization Osaka Hospital, Osaka, Japan"
      ],
      "name": "Yuki Tokuda"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan"
      ],
      "name": "Tasuku Nakabori"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan"
      ],
      "name": "Ryotaro Sakamori"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan"
      ],
      "name": "Kazuyoshi Ohkawa"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Osaka Keisatsu Hospital, Osaka, Japan"
      ],
      "name": "Masanori Miyazaki"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan"
      ],
      "name": "Shuhei Yamamoto"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan"
      ],
      "name": "Satoshi Shigeno"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan"
      ],
      "name": "Yuta Myojin"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan"
      ],
      "name": "Yuki Tahata"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan"
      ],
      "name": "Hayato Hikita"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan"
      ],
      "name": "Tetsuo Takehara"
    }
  ],
  "title": "Systemic immune profiling uncovers divergent mechanisms and predictive biomarkers of response to combination immunotherapies in hepatocellular carcinoma",
  "uid": "875260cc-cb0f-5ebe-8e7f-c8c0eb1891cb"
}