{
  "abstract": "Background We investigated the hypothesis that transforming growth factor β induced (TGFBI), an extracellular matrix protein secreted in the microenvironment of several tumors, can act as a secreted immune checkpoint (sIC) that contributes to the suppression of human antitumor T cell responses.Methods and results Serum TGFBI concentrations, measured by ELISA, were significantly higher in patients with colorectal cancer (CRC) and hepatocellular carcinoma than in healthy individuals and associated with poor overall survival. Strikingly, multiparametric flow cytometry analyses revealed that TGFBI was abundantly expressed by tumor cells or monocytes, and by various lymphoid cell types—including CD4 + or CD8+ T cells (including tissue-resident memory T cells), B cells, and natural killer cells—in patients with cancer. Importantly, ex vivo TGFBI neutralization significantly enhanced CD4+ and CD8+ T cell activation and function. Freshly isolated TGFBI-expressing CD4+ or CD8+ T cells demonstrated a markedly improved capacity to differentiate into functional effector cells—characterized by the acquisition of tissue-homing phenotypes—following TGFBI blockade. These findings suggest that TGFBI can establish an autocrine immunosuppressive loop within T cells, thereby limiting their differentiation and function. These mechanistic observations were further supported by human CRC organoid-based experiments, where TGFBI blockade improved expansion and tumor cell killing by major histocompatibility complex class I-restricted cytotoxic T cells.Conclusions Taken together, our data demonstrate that TGFBI acts as a sIC counter-regulating T cell activation, differentiation, and effector function, which can be restored by TGFBI blockade, with broad implications for novel immunotherapy strategies in solid tumors.",
  "authors": [
    {
      "affiliations": [
        "Department of Research, Advanced Diagnostic and Technological Innovation Translational Research Functional Departmental Area, Regina Elena Institute, Roma, Italy",
        "Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Maria Manuela Rosado"
    },
    {
      "affiliations": [
        "Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy"
      ],
      "name": "Eleonora Timperi"
    },
    {
      "affiliations": [
        "Department of Paediatric Haematology/Oncology and Cell and Gene Therapy, Bambino Gesu Pediatric Hospital IRCCS, Rome, Italy",
        "Department of Clinical Science and Translational Medicine, “Tor Vergata” University of Rome, Rome, Italy"
      ],
      "name": "Ombretta Melaiu"
    },
    {
      "affiliations": [
        "Istituto Superiore di Sanità, Rome, Italy"
      ],
      "name": "Sara Vitale"
    },
    {
      "affiliations": [
        "StromaCare Co, Lyon, France"
      ],
      "name": "Sophie Bachy"
    },
    {
      "affiliations": [
        "Department of Molecular Medicine, Sapienza University of Rome, Roma, Italy"
      ],
      "name": "Alessio Grimaldi"
    },
    {
      "affiliations": [
        "Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Mariachiara Corrado"
    },
    {
      "affiliations": [
        "Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Vanessa Mancini"
    },
    {
      "affiliations": [
        "Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Gabriela Leonti"
    },
    {
      "affiliations": [
        "Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Filippo Conti"
    },
    {
      "affiliations": [
        "Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Ilenia Cammarata"
    },
    {
      "affiliations": [
        "Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Ivana Celardo"
    },
    {
      "affiliations": [
        "Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, London, England"
      ],
      "name": "Stephanie Kucykowicz"
    },
    {
      "affiliations": [
        "Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, London, England"
      ],
      "name": "Gloryanne Aidoo-Micah"
    },
    {
      "affiliations": [
        "Department of Paediatric Haematology/Oncology and Cell and Gene Therapy, Bambino Gesu Pediatric Hospital IRCCS, Rome, Italy"
      ],
      "name": "Paula Gragera"
    },
    {
      "affiliations": [
        "Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Daniele Accapezzato"
    },
    {
      "affiliations": [
        "Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Maria Del Ben"
    },
    {
      "affiliations": [
        "Confocal Microscopy Core Facility, Bambino Gesu Pediatric Hospital, Roma, Italy"
      ],
      "name": "Valentina D’Oria"
    },
    {
      "affiliations": [
        "Flow Cytometry and Histology Core Facilities, Bambino Gesu Pediatric Hospital, Roma, Italy"
      ],
      "name": "Cristiano De Stefanis"
    },
    {
      "affiliations": [
        "DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy",
        "Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Istituto Pasteur Italia, Rome, Italy"
      ],
      "name": "Laura Forcina"
    },
    {
      "affiliations": [
        "Department of General and Specialistic Surgery, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Fabrizio Frattaroli"
    },
    {
      "affiliations": [
        "Department of General and Specialistic Surgery, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Andrea Picchetto"
    },
    {
      "affiliations": [
        "Department of General and Specialistic Surgery, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Massimo Chiaretti"
    },
    {
      "affiliations": [
        "Department of General and Specialistic Surgery, Sapienza University of Rome, Rome, Italy"
      ],
      "name": "Giancarlo D’Ambrosio"
    },
    {
      "affiliations": [
        "Department of Molecular Medicine, Sapienza University of Rome, Roma, Italy"
      ],
      "name": "Giuseppe Giannini"
    },
    {
      "affiliations": [
        "Department of Molecular Medicine, Sapienza University of Rome, Roma, Italy"
      ],
      "name": "Francesca Belardinilli"
    },
    {
      "affiliations": [
        "Hepato-Pancreato-Biliary Surgery Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy"
      ],
      "name": "Andrea Scarinci"
    },
    {
      "affiliations": [
        "Hepato-Pancreato-Biliary Surgery Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy"
      ],
      "name": "Gian Luca Grazi"
    },
    {
      "affiliations": [
        "DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy",
        "Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Istituto Pasteur Italia, Rome, Italy"
      ],
      "name": "Antonio Musarò"
    },
    {
      "affiliations": [
        "Institute of Immunity and Transplantation, Division of Infection and Immunity, UCL, London, England"
      ],
      "name": "Mala K Maini"
    },
    {
      "affiliations": [
        "Istituto Superiore di Sanità, Rome, Italy"
      ],
      "name": "Micol E Fiori"
    },
    {
      "affiliations": [
        "Department of Paediatric Haematology/Oncology and Cell and Gene Therapy, Bambino Gesu Pediatric Hospital IRCCS, Rome, Italy"
      ],
      "name": "Doriana Fruci"
    },
    {
      "affiliations": [
        "Cancer Research Centre Lyon (CRCL), Lyon, France"
      ],
      "name": "Anca Hennino"
    },
    {
      "affiliations": [
        "Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy",
        "Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Istituto Pasteur Italia, Rome, Italy"
      ],
      "name": "Vincenzo Barnaba"
    }
  ],
  "title": "Transforming growth factor β induced as a novel secreted immune checkpoint counterinhibiting human tumor-associated T cells",
  "uid": "bae247ff-10c3-54b5-935c-af49f2519013"
}