TGF-β-ρ-STAT1-LAIR2 axis has a "self-rescue" role for exhausted-CD8+ T cells in hepatocellular carcinoma

Background TGF-beta is related to the function of T cells in the tumor microenvironment. However, the characteristics of TGF-beta affecting the function of -CD8(+) T cells in hepatocellular carcinoma (HCC) have not been clearly resolved. Methods In this study, flow cytometry, mass cytometry, immunohistochemistry, RNA- seq, single-cell RNA-seq, assay for transposase-accessible chromatin with high throughput sequencing, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were used to study the regulatory effect and molecular mechanism of TGF-beta on HCC infiltrating -CD8(+) T cells. Results Here, we demonstrated that the overall effect of TGF-beta on -CD8(+) T cells in HCC was to activate p-p38 to induce exhaustion, but it also initiated cell-intrinsic resistance mechanisms: 1) TGF-beta upregulated the levels of p-STAT1 (S727) and promoted LAIR2 secretion; 2) the TGF-beta-p-STAT1-LAIR2 axis relieved -CD8(+) T cells from exhaustion, which we called "self- rescue"; 3) this "self-rescue" behavior showed time and dose limitations on TGF-beta stimulation, which was easily masked by stronger inhibitory signals; 4) the function of -CD8(+) T cells was improved by using TAK- 981 to amplify " self- rescue" signal. Conclusion Our study describes a "self-rescue" mechanism of -CD8(+) T cells in HCC against exhaustion and the good effects from amplifying this signal.