Open AccessA Safety Checkpoint to Eliminate Cancer Risk of the Immune Evasive Cells Derived from Human Embryonic Stem Cells
Author(s) -
He Jingjin,
Rong Zhili,
Fu Xuemei,
Xu Yang
Publication year - 2017
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2568
Subject(s) - embryonic stem cell , biology , immune system , regenerative medicine , humanized mouse , cancer research , immunology , immune tolerance , stem cell , microbiology and biotechnology , gene , genetics
Human embryonic stem cells (hESCs) hold great promise in the regenerative therapy of many currently untreatable human diseases. One of the key bottlenecks is the immune rejection of hESC‐derived allografts by the recipient. To overcome this challenge, we have established new approaches to induce immune protection of hESC‐derived allografts through the coexpression of immune suppressive molecules CTLA4‐Ig and PD‐L1 . However, this in turn raises a safety concern of cancer risk because these hESC‐derived cells can evade immune surveillance. To address this safety concern, we developed a safety checkpoint so that the immune evasive hESC‐derived cells in the graft can be effectively eliminated if any cellular transformation is detected. In this context, we knock‐in the suicidal gene herpes simplex virus thymidine kinase ( HSVTK ) into the constitutive HPRT locus of CP hESCs (knock‐in hESCs expressing CTLA4‐Ig and PD‐L1 ), denoted CPTK hESCs. Employing humanized mice (Hu‐mice) reconstituted with human immune system, we demonstrated that the CPTK hESC‐derived cells are protected from immune rejection. In addition, CPTK hESC‐derived cells can be efficiently eliminated in vitro and in vivo with FDA approved TK ‐targeting drug ganciclovir. Therefore, this new safety checkpoint improves the feasibility to use the immune evasive hESC‐derived cells for regenerative medicine. S tem C ells 2017;35:1154–1161