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: 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.