Differential expression of insulin-like growth factor type 1 receptor identifies heterogeneous intrahepatic regulatory T subsets in mouse hepatocellular carcinoma

The study characterized the expression of IGF1R in intrahepatic Tregs in a chemical-induced mouse HCC model and found two intrahepatic Treg subsets with differential IGF1R expression: IGF1Rhi Tregs and IGF1Rlo/- Tregs. These Treg subsets exhibited distinct cytokine production patterns, proliferation rates, and metabolic activities. Understanding regulatory T-cell (Treg)-mediated tumor tolerance is critical for designing immunotherapy against hepatocellular carcinoma (HCC). In this study, we characterized the expression of insulin-like growth factor type 1 receptor (IGF1R) in intrahepatic Tregs in a chemical-induced mouse HCC model. We found two intrahepatic Treg subsets with differential IGF1R expression: IGF1R(hi) Tregs and IGF1R(lo/-) Tregs. Functional assays indicated that compared with IGF1R(lo/-) Tregs, IGF1R(hi) Tregs produced more TGF-beta and IL-10 and were more proliferative in vivo. Furthermore, IGF1R(hi) Tregs exhibited higher phosphorylation of the mammalian target of the rapamycin complex 1 (mTORC1) in vivo. However, in vitro stimulation and immunosuppression assay revealed that the immunosuppressive capacity of the two Treg subsets was equivalent, as evidenced by comparable cytokine production and immunosuppressive effect over conventional T cells. The transcriptome sequencing analysis revealed up-regulation of genes that encode proteins essential for glycolysis, oxidative phosphorylation, and electron transport chain in IGF1R(hi) Tregs. Consistently, IGF1R(hi) Tregs produces more adenosine triphosphate (ATP), lactate, and reactive oxygen species (ROS). Furthermore, malignant cells in the tumor nodules induced IGF1R down-regulation in Tregs at the mRNA level. In summary, we identified the heterogeneity of intrahepatic Tregs in HCC which might play significant roles in tumor immunity.