{
  "abstract": "Spontaneously immunogenic hepatocellular carcinoma (HCC), identified by a dense immune cell infiltrate (ICI), responds better to immunotherapy, although no validated biomarker exists to identify these cases. We used machine learning (ML) to quantify ICI from standard H&E-stained tissue and evaluated its correlation with characteristics of the tumor microenvironment (TME) and clinical outcome from atezolizumab plus bevacizumab (A+B).We therefore employed a supervised ML algorithm on 102 pretreatment H&E slides collected from patients treated with A+B. We quantified tumor, stroma and immune cell counts/mm2 and dichotomized patients into ICI high and ICI low for clinicopathologic analysis. We correlated ICI signature with characteristics of the T-cell infiltrate (CD4+, FOXP3+, CD8+, PD1+) using multiplex immunohistochemistry in 62 resected specimens and evaluated gene expression profiles by bulk RNA sequencing in 44 samples.All patients treated with A+B were Child-Pugh A and received first-line A+B treatment for Barcelona Clinic Liver Cancer Stage C HCC (n=77, 75.5%) on a background of viral (n=53, 52%) and non-viral (n=49, 48%) liver disease. Median ICI density was 429.9 (IQR: 194.6–666.7) cells/mm2. Two-thirds of patients (n=67, 65.7%) had ICI counts≥236/mm2, derived as the optimal prognostic cut-off (ICI-high). Baseline characteristics, including disease etiology, liver function, performance status, stage, prior therapy and alpha-fetoprotein (AFP) levels, were comparable between ICI-high versus ICI-low patients. Patients with ICI-high demonstrated a significantly longer overall survival (OS) compared with ICI-low: 20.9 (95% CI: 13.8 to 27.9) versus 15.3 (95% CI: 6.0 to 24.6 months, p=0.026). Multivariable analyses demonstrated ICI-low status to remain as an independent prognostic parameter (adjusted HR (aHR): 2.02, 95% CI: 1.03 to 3.96) alongside AFP concentration (per 100 ng/mL: aHR 1.00, 95% CI: 1.00 to 1.00). ICI-high tumors were characterized by STC1 underexpression and enrichment in proinflammatory gene expression sets previously associated with response to immunotherapy. The proinflammatory environment identified by ICI status was not exclusively mediated by T-cell phenotype polarization as shown by a lack of correlation between ICI-high status and CD4+, CD4+FOXP3+, CD8+ and CD8+PD1+ T-cell density.In conclusion, we propose a ML-based algorithm to identify proinflamed HCC TMEs bearing a positive correlation with the patient’s OS. Digital characterization of the TME should be validated as a tool to improve precision delivery of anticancer immunotherapy.",
  "authors": [
    {
      "affiliations": [
        "Imperial College London Department of Surgery and Cancer, London, UK",
        "Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria"
      ],
      "name": "Bernhard Scheiner"
    },
    {
      "affiliations": [
        "Imperial College London Department of Surgery and Cancer, London, UK",
        "Phase 1 Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy"
      ],
      "name": "Pasquale Lombardi"
    },
    {
      "affiliations": [
        "Imperial College London Department of Surgery and Cancer, London, UK"
      ],
      "name": "Antonio D’Alessio"
    },
    {
      "affiliations": [
        "Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea"
      ],
      "name": "Gwangil Kim"
    },
    {
      "affiliations": [
        "Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway"
      ],
      "name": "Masoud Tafavvoghi"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria",
        "Ukrainian Institute for Systems Biology and Medicine, 04119 Kyiv, Ukraine"
      ],
      "name": "Oleksandr Petrenko"
    },
    {
      "affiliations": [
        "Imperial College London Department of Surgery and Cancer, London, UK"
      ],
      "name": "Robert D Goldin"
    },
    {
      "affiliations": [
        "Imperial College London Department of Surgery and Cancer, London, UK"
      ],
      "name": "Claudia A M Fulgenzi"
    },
    {
      "affiliations": [
        "Imperial College London Department of Surgery and Cancer, London, UK"
      ],
      "name": "Aria Torkpour"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria"
      ],
      "name": "Lorenz Balcar"
    },
    {
      "affiliations": [
        "Imperial College London Department of Surgery and Cancer, London, UK"
      ],
      "name": "Francesco A Mauri"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria"
      ],
      "name": "Katharina Pomej"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany"
      ],
      "name": "Vera Himmelsbach"
    },
    {
      "affiliations": [
        "Department of Internal Medicine II, Medical Center - University of Freiburg, Freiburg, Germany"
      ],
      "name": "Maryam Barsch"
    },
    {
      "affiliations": [
        "Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, University of Palermo, Palermo, Italy"
      ],
      "name": "Ciro Celsa"
    },
    {
      "affiliations": [
        "Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, University of Palermo, Palermo, Italy"
      ],
      "name": "Giuseppe Cabibbo"
    },
    {
      "affiliations": [
        "Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, South Korea"
      ],
      "name": "Jaekyung Cheon"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Steiermark, Austria"
      ],
      "name": "Anja Krall"
    },
    {
      "affiliations": [
        "Internal Medicine and Gastroenterology (IMuG), Including Centralized Emergency Service (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Kärnten, Austria"
      ],
      "name": "Florian Hucke"
    },
    {
      "affiliations": [
        "Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Italy",
        "Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy"
      ],
      "name": "Luca Di Tommaso"
    },
    {
      "affiliations": [
        "Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy"
      ],
      "name": "Monica Bernasconi"
    },
    {
      "affiliations": [
        "Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy",
        "Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy"
      ],
      "name": "Lorenza Rimassa"
    },
    {
      "affiliations": [
        "Leeds Institute of Medical Research at St James's (LIMR), School of Medicine, Faculty of Medicine and Health, University of Leeds, St James's University Hospita, Leeds, UK"
      ],
      "name": "Adel Samson"
    },
    {
      "affiliations": [
        "Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy"
      ],
      "name": "Bernardo Stefanini"
    },
    {
      "affiliations": [
        "Department of Pathology, Medical University of Vienna, Vienna, Austria"
      ],
      "name": "Behrang Mozayani"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria"
      ],
      "name": "Michael Trauner"
    },
    {
      "affiliations": [
        "Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria"
      ],
      "name": "Carolin Lackner"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Steiermark, Austria"
      ],
      "name": "Rudolf Stauber"
    },
    {
      "affiliations": [
        "Pathology Unit, IRCCS - Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"
      ],
      "name": "Francesco Vasuri"
    },
    {
      "affiliations": [
        "Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy",
        "Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"
      ],
      "name": "Fabio Piscaglia"
    },
    {
      "affiliations": [
        "Department of Internal Medicine II, Medical Center - University of Freiburg, Freiburg, Germany"
      ],
      "name": "Bertram Bengsch"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany"
      ],
      "name": "Fabian Finkelmeier"
    },
    {
      "affiliations": [
        "Internal Medicine and Gastroenterology (IMuG), Including Centralized Emergency Service (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Kärnten, Austria"
      ],
      "name": "Markus Peck-Radosavljevic"
    },
    {
      "affiliations": [
        "Department of Clinical Pathology, University Hospital of North Norway, Tromso, Norway"
      ],
      "name": "Lill-Tove Rasmussen Busund"
    },
    {
      "affiliations": [
        "Department of Histopathology, University College London Hospital, London, UK"
      ],
      "name": "Teresa Marafioti"
    },
    {
      "affiliations": [
        "Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany"
      ],
      "name": "Mohammad Rahbari"
    },
    {
      "affiliations": [
        "Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany"
      ],
      "name": "Mathias Heikenwalder"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria"
      ],
      "name": "Matthias Pinter"
    },
    {
      "affiliations": [
        "Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, South Korea"
      ],
      "name": "Hong Jae Chon"
    },
    {
      "affiliations": [
        "Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway",
        "Department of Clinical Pathology, University Hospital of North Norway, Tromso, Norway"
      ],
      "name": "Mehrdad Rakaee"
    },
    {
      "affiliations": [
        "Imperial College London Department of Surgery and Cancer, London, UK"
      ],
      "name": "David J Pinato"
    }
  ],
  "title": "Preliminary qualification of a machine learning-based assessment of the tumor immune infiltrate as a predictor of outcome in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab",
  "uid": "279f44b5-246d-523a-9d8d-3455667ac66e"
}