Transforming growth factor β induced as a novel secreted immune checkpoint counterinhibiting human tumor-associated T cells
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: 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
- Laura Forcina (ORCID: https://orcid.org/0000-0003-3446-7672)
- Gian Luca Grazi (ORCID: https://orcid.org/0000-0002-3279-0313)
- Vincenzo Barnaba (ORCID: https://orcid.org/0000-0001-7908-8049)
- Ilenia Cammarata
- Doriana Fruci (ORCID: https://orcid.org/0000-0003-3388-7296)
- Daniele Accapezzato (ORCID: https://orcid.org/0000-0002-0983-3610)
- Eleonora Timperi (ORCID: https://orcid.org/0000-0002-8357-6587)
- Sara Vitale (ORCID: https://orcid.org/0000-0002-9011-9042)
- Francesca Belardinilli (ORCID: https://orcid.org/0000-0003-4966-7044)
- Maria Manuela Rosado (ORCID: https://orcid.org/0000-0002-2779-3157)
- Antonio Musarò (ORCID: https://orcid.org/0000-0002-2944-9739)
- Stephanie Kucykowicz (ORCID: https://orcid.org/0000-0002-8849-218X)
- Gloryanne Aidoo-Micah (ORCID: https://orcid.org/0000-0001-5696-9943)
- Micol Eleonora Fiori (ORCID: https://orcid.org/0000-0002-1813-7035)
- Andrea Picchetto (ORCID: https://orcid.org/0000-0003-4300-9286)
- Ivana Celardo (ORCID: https://orcid.org/0000-0003-1412-8569)
- Fabrizio Maria Frattaroli
- Vanessa Mancini (ORCID: https://orcid.org/0000-0002-8050-3024)
- Sophie Bachy
- Mala K. Maini (ORCID: https://orcid.org/0000-0001-6384-1462)
- Massimo Chiaretti (ORCID: https://orcid.org/0000-0002-9689-7566)
- Paula Gragera (ORCID: https://orcid.org/0009-0007-5088-1757)
- Alessio Grimaldi (ORCID: https://orcid.org/0000-0001-5066-564X)
- Filippo Conti
- Valentina D’Oria
- Giancarlo D’Ambrosio
- Maria Del Ben
- Andrea Scarinci
- Gabriela Leonti
- Mariachiara Corrado
- Cristiano De Stefanis
- Giuseppe Giannini
- Ombretta Melaiu
Institutions
- Università Cattolica del Sacro Cuore (IT)
- University of Rome Tor Vergata (IT)
- Istituto Superiore di Sanità (IT)
- Bambino Gesù Children's Hospital (IT)
- Centre de Recherche en Cancérologie de Lyon (FR)
- MemorialCare Health System (US)
- Cellular Therapeutics (United Kingdom) (GB)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto Pasteur (IT)
- Institute of Infection and Immunity (CA)
- University College London (GB)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Journal for ImmunoTherapy of Cancer
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1136/jitc-2025-012668
- Primary Topic
- TGF-β signaling in diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fondazione Italiana Sclerosi Multipla
- Cancer Research UK
- Fondation pour la Recherche Médicale
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro