Hello! This week I’ll be discussing Induced Pluripotent Stem Cells (iPSCs) and CD47, cancer’s mighty shield.
Induced Pluripotent Stem Cells
Induced Pluripotent Stem Cells (iPSCs) are blood or skin cells that are reprogrammed into a pluripotent stem cell state (i.e., they can self-renew and differentiate into any cell of the body). Four protein transcription factors, Oct3/4, Sox2, Klf4, and c-Myc, are responsible for pluripotency and are transduced (the viral transfer of genetic material) into blood or skin cells to forge iPSCs.
Allogeneic (foreign), iPSC-derived CAR T-cells present a major problem: the possibility of a severe immune reaction. Previously, I’ve discussed two ways of resolving this issue. Now, I’ve found that there may exist another method. Dr. Sonja Schrepfer and her team at the University of California at San Francisco demonstrated that both mouse and human iPSCs lose their immunogenicity (ability to provoke an immune response) when their HLA class I and II genes are inactivated and CD47 is overexpressed. (Deuse et al., 2019)
CD47: Cancer’s Mighty Shield
CD47 is a receptor known for its immuno-suppressive abilities. As a result, it is widely expressed in cancer and is considered an ideal target for immunotherapy. CD47 is one of cancer’s weapons used to defend itself against our immune system. (Hayat et al., 2020, p. 47) However, can we adapt this weapon to cure cancer?
CD47 could be what “Off-the-Shelf” CAR T-cells need to express to escape immune rejection.
The team of scientists studied CD47 overexpression in mouse models. They first tested the CD47 engineered cells in Natural Killer (NK) cell toxicity trials. (NK cells are partly responsible for the bodies’ rejection of allogeneic cell therapies.) The CD47 overexpression prevented any mouse iPSC-induced NK cell IFN- release, a protein that is responsible for activating fighter immune cells. Next, human iPSCs engineered with HLA class I and II deletion and CD47 overexpression were examined in mouse models. No measurable NK cell response was found. (Deuse et al., 2019)
Further Research Needed
CD47 engineered “Off-the-Shelf” CAR T-cells help get past the hurdle of an NK cell response. Further research must be conducted to determine whether there is a significant T cell response to the CD47 engineered cells. T cells contain T cell receptors which hunt for cells with non-matching HLA molecules. While the engineered cells lack HLA class I and II molecules, there are minor histocompatibility molecules which may activate a T cell (Host v. Graft) response.
Further research must also be conducted to determine whether HLA class I and II deletion is needed. Would CD47 overexpression alone be enough to halt NK cell responses? Additionally, we do not understand the consequences of cells that will evade immune responses indefinitely, but genetic “kill switches” could be introduced into the “Off-the-Shelf” CD47 CAR T-cells.
Cancer mounts a robust defense against our immune system, but interestingly, that’s exactly what “Off-the-Shelf” CAR T-cells must do too. Perhaps we can continue to learn from cancer’s defense mechanisms to make more formidable immune soldiers. Be sure to tune in next week as I continue to hunt for the perfect method to create “Off-the-Shelf” CAR T-cells.