Transforming growth factor β induced as a novel secreted immune checkpoint counterinhibiting human tumor-associated T cells
Year: 2026
Type: article
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: Maria Manuela Rosado, Eleonora Timperi, Ombretta Melaiu, Sara Vitale, Sophie Bachy, Alessio Grimaldi, Mariachiara Corrado, Vanessa Mancini, Gabriela Leonti, Filippo Conti, Ilenia Cammarata, Ivana Celardo, Stephanie Kucykowicz, Gloryanne Aidoo-Micah, Paula Gragera, Daniele Accapezzato, Maria Del Ben, Valentina D’Oria, Cristiano De Stefanis, Laura Forcina, Fabrizio Frattaroli, Andrea Picchetto, Massimo Chiaretti, Giancarlo D’Ambrosio, Giuseppe Giannini, Francesca Belardinilli, Andrea Scarinci, Gian Luca Grazi, Antonio Musarò, Mala K Maini, Micol E Fiori, Doriana Fruci, Anca Hennino, Vincenzo Barnaba
Institutions: Instituto Nazionale Tumori Regina Elena, Sapienza University of Rome, Università Cattolica del Sacro Cuore, University of Rome Tor Vergata, Bambino Gesù Children's Hospital, Istituto Superiore di Sanità, University College London, Istituto Pasteur, Centre de Recherche en Cancérologie de Lyon
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
Funders: Fondazione Italiana Sclerosi Multipla, Cancer Research UK, European Commission, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Ministero dell’Istruzione, dell’Università e della Ricerca, Associazione Italiana per la Ricerca sul Cancro, Ministero dell'Università e della Ricerca, Inserm Transfert
OpenAlex ID: W7148541236