What are regulatory T cells (Treg) regulating in cancer and why?

The role regulatory T cells (Treg) play in cancer development and progression is not clear. Earlier evidence suggested that CD4(+)FOXP3(+)CD25(high) Treg accumulate in tumors and the peripheral blood of patients with cancer and through suppression of anti-tumor immune responses promote tumor growth. However, more recent data indicate that in certain cancers, such as colorectal carcinoma (CRC), Treg suppress bacteria-driven inflammation which promotes carcinogenesis and thus benefit the host. Treg appear to play a dual role in cancer. This might explain why the frequency and functions of Treg are associated with a poor prognosis in some cancers but with favorable outcome in others. The clinical and prognostic significance of Treg in cancer depends on environmental factors, including infectious agents, tumor-derived products and locally-produced cytokines, which shape the nature of immune responses, including Treg generation, recruitment and survival. Adaptive or inducible (i) Treg or Tr1 are the major subset(s) of Treg present in cancer. These iTreg are a distinct subset of regulatory cells that phenotypically and functionally differ from FOXP3(+) natural (n) Treg responsible for peripheral tolerance. They mediate powerful suppression of effector T cells via diverse mechanisms, produce immunosuppressive cytokines, notably TGF-β as well as prostaglandin E2 and adenosine, and are resistant to apoptosis or oncological therapies. Strategies for silencing of Tr1 in patients with cancer will require novel approaches that can selectively deplete these cells or block molecular pathways they utilize.