Separating the Good from the Bad: Tumor-Infiltrating Tregs Have Increased Fucosylation

Regulatory T cells (Treg) undergo metabolic adaptation within the tumor microenvironment, altering glucose, lipid, lactate, and amino acid metabolism in response to the nutrient-poor and hypoxic conditions encountered. These changes may provide therapeutic opportunities to target cancer-promoting Tregs in tumor tissues specifically while sparing peripheral Tregs that promote immune homeostasis (1). However, strategies focused on disrupting glucose metabolism in tumor-infiltrating Tregs, such as by targeting the PI3K–AKT–mTOR pathway, have been suspended because of immune-related adverse events (2). However, another metabolism-based strategy to target Tregs, inhibition of lipid metabolism via CD36 mAb treatment, specifically reduced the abundance of tumor-infiltrating Tregs in mouse models (1). Thus, targeting metabolic pathways holds promise for selectively altering Treg populations in tumors with the identification of better targets.

In this issue, Pinioti and colleagues uncover a new metabolic adaption of tumor-infiltrating Tregs, namely enhanced fucosylation (3). Using a genetic screen targeting metabolic genes in Tregs, they identify the GDP-fucose transporter Slc35c1 as a positive regulator of Foxp3, which is the key transcription factor for Treg identity (3). In addition, knockout of fucosyltransferases expressed in Tregs caused reduced Foxp3 expression and the examination of tumors in mice showed that tumor-infiltrating Tregs harbored increased levels of fucosylation. Cas9-mediated editing of Slc35c1 in Tregs or in vivo inhibition of fucosylation in mice using 2F-peracetyl fucose, led to reduced Treg accumulation in tumors and improved tumor control in mice (3). While Slc35c1 has been shown to regulate activation and migration of conventional T cells through posttranslational modification of the T-cell receptor (4), programmed cell death-1 (PD-1; ref. 5), and other cell surface proteins, this study reveals a critical role for Slc35c1 in Tregs. This provides mechanistic insight into previous studies showing that fucosylation of Tregs ex vivo can enhance the control of GVHD (6).

The stability of PD-1 cell surface expression was recently shown to require fucosylation (5). Noting reduced levels of PD-1 on Slc35c1-deficient Tregs, and the critical role PD-1 may play in maintaining Foxp3 expression and Treg function, Pinioti and colleagues generated Tregs reconstituted with a fucosylation-deficient version of PD-1. Strikingly, Tregs harboring the mutant PD-1 were unable to effectively suppress antitumor responses, implicating PD-1 as a critical target of fucosylation for Treg-mediated suppression in cancer (3). Nevertheless, as pointed out by the authors, PD-1, while a critical fucosylated protein in Tregs, is likely only one of many protein targets that contribute to Treg function. Pinpointing the mechanism underlying the effect of fucosylation on Tregs will undoubtedly reveal new regulators of their suppressive activity in tumors.

The translational importance of the findings of Pinioti and colleagues is increased by the demonstration that high fucosylation signatures in human cancers are associated with worse prognoses, indicative of the potential for targeting fucosylation as a mechanism to target tumor-infiltrating Tregs (3). Overall, this study identifies a promising metabolism-based approach to disrupt Tregs selectively in tumors. Pairing fucosylation inhibitors with other immunotherapies may improve their efficacy by diminishing the Treg-mediated suppression of antitumor responses without compromising immune homeostasis in patients with cancer.

No disclosures were reported.