A weak Foxp3 hypomorph enhances spontaneous and therapeutic immune surveillance of cancer in mice

It is well established that therapeutic impairment of Foxp3+ regulatory T cells (Treg) in mice and humans favors immune rejection of solid tumors. Less explored are the genetic associations between Foxp3 allelic variants and tumor incidence, only sporadically reported in human studies. In this work, we tested and demonstrate that Foxp3fGFP, an allele classified as hypomorphic in Th1 inflammatory contexts but not affecting health at steady state, confers increased anti-tumor immunity. Our conclusions stem out of the analysis of three tumor models of different tissue origin, in two murine genetic backgrounds. When compared to wild type animals, mice carrying the Foxp3fGFP allele spontaneously delay, reduce or prevent primary tumor growth, decrease metastasis growth and potentiate the response to anti-CTLA4 monotherapy. These findings suggest that allelic variance at the Foxp3 locus may have significant impact on cancer incidence and/or the success of cancer-immunotherapies in humans.