Human hepatocellular carcinoma-infiltrating CD4+CD69+Foxp3- regulatory T cell suppresses T cell response via membrane-bound TGF-β1

Tumors can recruit, induce, and expand regulatory T cells (Tregs) to suppress antitumor immune responses for survival and progression. The complicated tumor-related Treg subsets and their functional mechanisms are not fully addressed yet. We have previously identified a novel CD4(+)CD69(+)CD25(-)Foxp3(-) Treg subset in tumor-bearing mice, which suppresses CD4 T cell response via membrane-bound transforming growth factor beta 1 (mTGF-beta 1) and then promotes tumor progression. In hepatocellular carcinoma patients, here, we identified tumor-infiltrating human CD4(+)CD69(+) Tregs which represent similar to 67.2 % of tumor-infiltrating CD4 T cells that is significantly higher than conventional CD4(+)CD25(+)Foxp3(+) Tregs. They expressed mTGF-beta 1, PD-1, and CTLA-4, but not CD25 or Foxp3, and only produced a little interleukin (IL)-10 and TGF-beta 1. More importantly, they significantly suppressed CD4 T cell response via mTGF-beta 1 in vitro. Furthermore, the percentage of these CD4(+)CD69(+) Tregs in tumor tissue was significantly correlated with tumor progression, which is more pronounced at the late stage of cancer patients. Thus, we have identified a tumor-induced new population of human CD4(+)CD69(+) Tregs in cancer patients with phenotype of CD25(-)Foxp3(-)mTGF-beta 1(+)CTLA-4(+)PD-1(+), and these Tregs can suppress antitumor immune response via mTGF-beta 1. Our results not only enrich the family of Treg subsets, providing new mechanistic insight to tumor-induced immune suppression in human, but also suggest a potential target for cancer immunotherapy. CD4(+)CD69(+)Foxp3(-) regulatory T cells were identified in hepatocellular carcinoma patients. These Treg cells inhibit T cell response via membrane-bound TGF-beta. The percentage of these cells was significantly correlated with tumor progression. The percentage of these cells was higher than conventional CD4(+)CD25(+)Foxp3(+) Tregs. These Treg cells not only exist in tumor-bearing mice, but also in cancer patients.