Evaluating the immune checkpoint TIGIT as a novel target in pulmonary fibrosis - 09/05/26

Idiopathic pulmonary fibrosis (IPF) represents the most frequent and severe type of lung fibrosis, with limited therapeutic options [1 Lancet Respir Med. 2020;8:424-25.

Haga clic aquí para ir a la sección de Referencias] . While the immune system's role in IPF remains debated, its contribution via the production of key fibrotic mediators is established. In particular, regulatory T cells (Tregs) secrete transforming growth factor beta (TGF-β) and interleukin (IL-) 10, promoting the proliferation of fibroblasts. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an immune checkpoint implicated in different pathological contexts, notably cancer. High TIGIT expression marks enhanced Tregs’ suppressive functions, associated with fibrinogen-like protein 2 and IL-10 production upon ligation [2 Front Immunol. 2021;12:699895.

Haga clic aquí para ir a la sección de Referencias] . Building on this, we aimed to characterize TIGIT expression in the lungs of IPF patients and to assess the impact of its inhibition on lung fibrosis progression.

Transcriptomic data from the IPF atlas were reanalysed to characterize TIGIT gene expression in lung immune cells. TIGIT levels were also quantified in bronchoalveolar lavage fluid (BAL) cells and correlated with disease severity. Pulmonary fibrosis was induced in FoxP3-GFP and humanized TIGIT (hTIGIT) knock-in mice. Lungs and BAL were collected 7 or 14 days (D) after intranasal exposure to bleomycin (BLM), and immunophenotyping was performed using flow cytometry. hTIGIT mice were injected at D ₈ and D ₁₁ with a human TIGIT antagonist “Tiragolumab” or an isotype control, and lung fibrosis was assessed.

TIGIT is most highly expressed by Tregs in the lungs and is significantly upregulated in IPF relative to healthy donors. The percentage of TIGIT+ Tregs is elevated in the BAL of IPF patients, but no correlation is revealed with respiratory function, sex, or smoking status. In both mouse models, Treg count increases upon BLM stimulation, and the percentage of TIGIT+ Tregs is significantly enhanced during the fibrotic phase (D ₁₄ ). Interestingly, TIGIT+ cells display an upregulated expression of FoxP3 and CD ₂₅ as compared to TIGIT- cells, and an increased secretion of IL-13 and IL-10 in lungs at D ₁₄ . Treatment of hTIGIT mice with Tiragolumab does not affect the development of lung fibrosis. Specifically, no changes were observed in body weight, collagen production, or in the number and activation status of pulmonary myeloid and lymphoid cells.

TIGIT emerges as a promising marker of pulmonary Treg fibrotic activity in IPF, however, treatment of humanized mice with Tiragolumab does not affect lung fibrosis progression under our experimental conditions. More studies are needed to evaluate the effects of other TIGIT modulators on the fibrotic activity of immune cells, both in preclinical mouse models and in primary human lung cells.