FOXP3: Critical for the Immunosuppressive Function of Regulatory T cells
The FOXP3 gene has been characterized in both humans and mice. In humans, FOXP3 mutation leads to the development of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX).3 Treg cell number appears normal in IPEX, but the ability of Treg to suppress effector T cells is significantly impaired.4 In contrast to humans, FOXP3 mutation in mice results in depletion of CD4+ CD25+ T cells.5 In both humans and mice, FOXP3 loss-of-function mutation leads to early onset fatal immune dysfunction.
The hypoxic tumor microenvironment promotes recruitment of FOXP3+ Treg, which preferentially infiltrate and accumulate within tumors.6 These FOXP3+ Treg can play dueling roles in the immune response to cancer in that they may essentially aid tumor growth by suppressing effector immune response, or they may protect against tumor progression by downregulating inflammation.7 This is demonstrated in that FOXP3+ Treg are associated with reduced overall survival in breast, renal, and cervical cancer as well as in melanoma, but contrastingly are associated with improved survival in colorectal, head and neck, and esophageal cancers.8 Thus, the prognostic value of FOXP3+ Treg may depend on tumor site, stage, and molecular subtype.
Treg have been the target of various cancer therapies, and anti-CD25 antibodies or low dose chemotherapy, for example, may effectively deplete Treg.9 However, nonspecific global depletion of Treg can also potentiate autoimmunity. More recent findings regarding the role of FOXP3 in Treg function have allowed for development of therapies which more specifically target Treg within the tumor microenvironment. Multiple small molecule drugs targeting FOXP3 have achieved downregulation of FOXP3 expression as well as protection against tumor implantation in mouse models.9 In addition to small molecules, FOXP3 has also been targeted by vaccine therapy, which can specifically deplete the tumoral (but not peripheral) Treg, potentially preventing the widespread autoimmunity observed with nonspecific Treg depletion.9 Assuming FOXP3+ Treg can be efficiently and specifically isolated and grown in culture, histone deacetylase inhibitors may also provide an opportunity to maintain or enhance functional stability of infused Treg cells.7