Regulatory T cells (Treg) have evolved to keep immune responses to foreign antigens (e.g., viruses, commensal bacteria, etc.) in check. This allows a protective but transient inflammation and tissue repair cycle to be appropriately curtailed and the system reset (i.e., homeostasis), thus preserving self-tolerance.

 

Cancers – with their many genetic alterations – frequently present themselves to the immune system as ‘foreign’. However, tumors are also capable of 'adapting' and co-opting immune suppressive mechanisms to evade eradication by the immune system.

 

Numerous studies of human cancers have found Treg cell accumulation in and around tumors; this observation repeatedly correlates with poor patient prognosis in many cancer types, including, among others, melanoma, lung and breast cancers. This data has triggered research into the manipulation of Treg cells, in an effort to provoke a therapeutic anti-tumor immune response. The objective is to put an end to the ‘immune privileged’ state under which many cancers thrive.

 

Strategies to suppress Treg cells have included modulating cytokine signaling, depletion with antibodies or treatment with cytotoxic agents. However, these approaches frequently also impact the cell populations required for a robust immune response. Novel approaches to selectively interfere with tumor-associated Treg cells are therefore of interest.  A particularly important mechanism by which tumors stimulate the generation of Treg is through an enzyme called indoleamine-2,3-dioxygenase-1 (IDO-1), which is upregulated in tumors and lymph nodes.

 

Treg cells are characterized by the expression of the forkhead transcription factor (FOXP3) which was shown by the Rudensky and Sakaguchi laboratories to be both necessary and sufficient for these cells to repress inflammatory immune cells. Treg cells also express a number of other cell surface proteins such as the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) and cytotoxic T lymphocyte antigen 4 (CTLA4), an important inhibitor of effector T cell function. While the system is intricate, interfering with FOXP3 function represents an attractive and perhaps specific approach to unleashing a therapeutic anti-tumor immune response.