Abstract
Regulatory T cells (T(reg) cells) represent a primary barrier to the development of effective antitumor immunity. Here, we report that reprogramming T(reg) cells by shifting the expression of FOXP3 from its full-length isoform (FOXP3(FL)) to a short isoform with exon 2 skipped (FOXP3(dE2)) promotes CD8 T cell-mediated antitumor immunity. FOXP3(dE2) mRNA expression in triple-negative breast cancer tissue positively correlated with overall patient survival. Mice expressing only the FOXP3(dE2) isoform were resistant to the development of multiple types of tumors. Tumor-infiltrating T(reg) cells expressing the FOXP3(dE2) isoform exhibited lower immunosuppressive activity and promoted CD8 T cell activation. In addition, we designed a morpholino oligo to induce FOXP3 exon 2 skipping, which similarly enhanced antitumor activity in mouse tumor models and the killing capacity of autologous tumor-infiltrating T cells against patient-derived tumor organoids. Our results suggest that promoting FOXP3(dE2) expression reprograms T(reg) cells to T helper-like cells, thereby enhancing antitumor immunity.