Tolerance to Fetuses and Tumors is Similar and Orchestrated by Regulatory T Cells

Embryos and tumors are both masses of dividing cells expressing foreign antigens, but are not rejected by the immune system. We hypothesized that similar tolerogenic mechanisms prevent their rejection. Global comparison of fetal and tumor microenvironments through transcriptomics revealed strikingly similar and dramatic decreases in expression of numerous immune-related pathways, including antigen presentation and T cell signaling. Unsupervised analyses highlighted the parallel kinetics and similarities of immune signature down-regulation, from the very first days after tumor or embryo implantation. Besides up-regulated signatures related to cell proliferation, the only significant signatures shared by the two conditions across all biological processes and all time points studied were down-modulated immune response signatures. Regulatory T cell depletion completely reverses this immune down-modulation to an immune up-regulation that leads to fetal or tumor immune rejection. We propose that evolutionarily selected mechanisms that protect mammalian fetuses from immune attack are hijacked to license tumor development.