Regulatory T (Treg) cells are an immunosuppressive subset of CD4+ T cells and are an essential component of the immune system in maintaining self-tolerance and immune homeostasis. However, tumor infiltrating Tregs also suppress effective anti-cancer immunity, thus promoting tumor development and progression. Given the importance of Tregs in suppression of antitumor immune responses, numerous strategies have been proposed to target Tregs to enhance antitumor immunity. However, depletion of Tregs has provided moderate or limited clinical benefits, suggesting that systemic depletion of these cells is not a favorable strategy due to the critical role of Tregs in maintaining immune homeostasis.
Tregs are characterized by the expression of the master transcription factor FOXP3. Human FOXP3 gene encodes two major isoforms through mRNA alternative splicing: a long full-length isoform (FOXP3L) and a shorter isoform lacking the exon 2 region (FOXP3S). Interestingly, bioinformatics analysis of human breast cancer datasets reveals that FOXP3S mRNA expression in human breast cancer is positively correlated with clinical outcomes. To parse the enigmatic function of the difference in the two Foxp3 isoforms, Xiongbin Lu’s group generated a genetically engineered mouse line model expressing only the Foxp3S isoform. Strikingly, they found that the Foxp3S mice were resistant to the development of breast, lung, colon, and melanoma tumors, while the littermate wildtype mice expressing Foxp3L exhibit significant tumor growth.
They hypothesize that promoting FOXP3S isoform expression will reprogram tumor-reactive Tregs, convert the immune suppressive Tregs to tumor-specific T helpers, and thus promote antitumor immunity. To test this, they will use unique mouse lines expressing only Foxp3S and patient-derived organoids. Immune cell profile and functional analysis, single cell transcriptomics and gene expression splicing will be conducted. Ultimately, reprograming tumor-reactive Treg function may provide a more effective, targeted approach to promote antitumor immunity without inducing systemic adverse consequences.
Du J, Wang Q, Yang S, Chen S, Fu Y, Spath S, Domeier P, Hagin D, Anover-Sombke S, Haouili M, Liu S, Wan J, Han L, Liu J, Yang L, Sangani N, Li Y, Lu X, Janga SC, Kaplan MH, Torgerson TR, Ziegler SF, Zhou B. FOXP3 exon 2 controls Treg stability and autoimmunity. Sci Immunol. 2022.