Regulatory T (T_reg) cells that express a shortened form of FOXP3 can promote cytotoxic T cell-mediated antitumor activity, according to new research involving mice. The study also showed that a synthetic molecule that reprogrammed T_reg cells to express the shorter FOXP3 variant boosted antitumor activity in mouse models and patient-derived tumor organoids. These findings could inform treatments to overcome tumor immunosuppression by T_reg cells that express full-length FOXP3 (FOXP3^FL). While mice only carry a single version of FOXP3^FL, humans express a form of FOXP3 that lacks exon 2 (FOXP3^dE2) and is associated with proinflammatory functions and autoimmune disease. By contrast, T_reg cells that express FOXP3^FL inhibit inflammation, which can dampen antitumor immunity. To investigate how FOXP3^dE2 affects tumor immune responses, Yujing Li and colleagues examined data from patients with triple-negative breast cancer and from a broader cancer genome atlas. They determined that FOXP3^dE2 expression was linked to better patient survival in multiple cancers, while FOXP3^FL expression was associated with poorer outcomes. Furthermore, genetically modified mice with T_reg cells that express FOXP3^dE2 (dE2 T_reg cells) were resistant to tumor growth in several types of cancers. The researchers examined immune cells from the tumor microenvironment and found that dE2 T_reg cells boosted the activation and accumulation of tumor-infiltrating cytotoxic T cells. In addition, dE2 T_reg cells downregulated genes related to immune suppression and T_reg cell stability and upregulated helper T cell features. Li et al. designed a synthetic molecule known as a morpholino, which can bind to FOXP3 mRNA and skip the expression of exon 2 – thus shifting FOXP3^FL to FOXP3^dE2. Morpholino treatment enhanced antitumor immunity in mice and in patient-derived breast cancer and colorectal cancer tumor organoids. “Our study suggests that [morpholino]-mediated FOXP3 isoform shifting is a potentially promising immunotherapeutic approach for cancer treatment,” the authors write.

For reporters interested in trends, a Science Immunology study published in 2022 by some of the same authors examined the role of exon 2 in FOXP3 and T_reg cell function: https://www.science.org/doi/10.1126/sciimmunol.abo5407