TGF-β1 induces PD-1 expression in macrophages through SMAD3-STAT3 cooperative signaling in chronic inflammation.

Programmed cell death protein 1 (PD-1), a coinhibitory T-cell checkpoint, is also expressed on macrophages (Mφ) in pathogen- or tumor-driven chronic inflammation. Increasing evidence underscores the importance of PD-1 on Mφ for dampening immune responses. However, the mechanism governing PD-1 expression in Mφ in chronic inflammation remains largely unknown. TGF-β1 (transforming growth factor-β1) is abundant within chronic inflammatory microenvironments. Here, based on public databases, significant positive correlations between PDCD1 and TGFB1 gene expression were observed in most human tumors. Of note, among immune infiltrates, Mφ as the predominant infiltrate expressed higher PDCD1 and TGFBR1/TGFBR2 genes. MC38 colon cancer and S. japonicum infection were used as experimental models for chronic inflammation. PD-1hi Mφ from chronic inflammatory tissues displayed an immunoregulatory pattern and expressed a higher level of TGF-β receptors. Either TGF-β1-neutralizing antibody administration or Mφ-specific Tgfbr1 knockdown largely reduced PD-1 expression on Mφ in animal models. We further demonstrated that TGF-β1 directly induced PD-1 expression on Mφ. Mechanistically, TGF-β1-induced PD-1 expression on Mφ was dependent on SMAD3 and STAT3, which formed a complex at the Pdcd1 promoter. Collectively, our study shows that Mφ adapt to chronic inflammation through TGF-β1-triggered cooperative SMAD3-STAT3 signaling that induces PD-1 expression and modulates Mφ function.