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Induction and maintenance of immunologic tolerance/evasion for genetically foreign cells and tissues (e.g. skin allografts) in humans remains a conundrum. Nature has solved this problem in a variety of forms and in different biological contexts. This includes many types of cancer that have low or absent MHC expression. The receptivity of the maternal decidua to the invading genetically foreign fetus is reminiscent of the receptivity of a secondary site to a cancer micrometastasis. The process of placenta proliferation, migration, and invasion, and the remodeling of neovascularization at the implantation site, share many conserved programs with cancer cell metastasis formation (e.g. melanoma). It is evident that immune checkpoint factors regulating cancer also play essential roles in the placenta (e.g. PDL1, CTLA-4, KIR, IDO). The placenta may be the most robust and ubiquitous immune-evading organ that has ever evolved. For example, the long sought-after goal of creating ‘off-the-shelf’ donor cells that are invisible to the immune system (‘universal cells’), which has enormous potential for allogeneic skin grafts, is coming into focus with the advent of iPSCs, CRISPR, and other gene-editing technologies by mimicking maternal-fetal immune tolerance and tumor immune evasion.

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