A specific population of immune regulatory T cells (Treg) expressing low levels of the FOXP3 transcription factor, are triggered by intestinal bacteria and initiate anti-tumour immune responses in colorectal cancers according to the study “Two FOXP3 CD4 T cell subpopulations distinctly control the prognosis of colorectal cancers,” recently published in the journal Nature Medicine.
The human immune system, finely tuned to activate immune cells and launch responses against cancer cells or pathogens, has evolved to develop counteracting mechanisms that ultimately regulate its activity and shut down its response before it can induce damage.
Treg cells are key players in immune regulation but can be detrimental when fighting cancer cells because they also hold the capacity to suppress the cells attacking tumors. Research has already shown that tumor-infiltrating Tregs are poor prognosis indicators for several cancers.
But in colorectal cancers the role of Treg cells seems the opposite: they seem to fuel anti-tumoral responses.
To investigate the contradiction, researchers led by Professor Shimon Sakaguchi at the Osaka University’s Immunology Frontier Research Center, studied T cells expressing a transcription factor called FOXP3, considered a master gene of Treg cells.
Reseachers found among the FOXP3+ cells that infiltrated deeply into colorectal cancers tumors, a group of Tregs expressing low levels of FOXP3 that promoted anti-cancer immunity. While the majority of FOXP3+ T-cells are characterized as immunosuppressive Treg cells, FOXP3-low expressing cells have the opposite effect and augment immune responses. While the prognosis for colorectal tumors with abundantlow FOXP3-Treg cells was good, for those with high FOXP3-Treg cells it was low. The FOXP3-low expressing cells were induced by inflammatory cytokines, such as IL-12, which in turn was induced by intestinal bacteria attaching to colorectal cancers.
An accurate quantification of the levels of FOXP3-low Tregs could become a useful marker for assessing immune status in cancer tissues. It might also allow fine-tuning of immunotherapy treatments, because cancer immunotherapy is effective for only some types of tumors.
Additionally, because intestinal bacteria may play a key role in inducing low FOXP3 Tregs cells, future prevention of intestinal cancers could happen by controlling intestinal bacteria.