Preventing the Rejection of Embryonic Stem Cell Derivatives – Take Two


Yesterday I blogged about the paper from Yang Xu’s group that used genetically engineered embryonic stem cells to make adult cell types that were not rejected by the immune systems of mice with humanized immune systems. I would like to say a bit more about this paper before I leave it be.

First of all, Xu and his colleagues engineered the cells to express the cell-surface protein PD-L1, which stands for programmed cell death ligand 1 (also known as CD274), and another protein called CTLA4-Ig. The combination of these two proteins tends to make these cells invisible to the immune system for all practical intents and purposes.

PD-L1, however, is used by tumor cells to evade detection by the immune system. For example, increased expression of PD-L1 is highly correlated with the aggressiveness of the cancer. One particular experiment examined 196 tumor specimens that had been extracted from patients with renal cell carcinoma (kidney tumors). In these tumor samples, high expression of PD-L1 was positively associated with increased tumor aggressiveness and a those patients that had higher expression of PD-L1 have a 4.5-fold increased risk of death (see Thompson RH, et al., Proc Natl Acad Sci USA 101 (49): 17174–9). In patients with cancer of the ovaries, those tumors with higher PD-L1 expression had a significantly poorer prognosis than those with lower PD-L1 expression. The more PD-L1 these tumors expressed, the fewer tumor-hunting T cells (CD8+ T cells) were present (see Hamanishi J, and others, Proc Natl Acad Sci USA 104 (9): 3360–5).

So the Xu paper proposes that we introduce genetically engineered cells, which are already at risk for mutations in the first place, into the body, that constitutively express PD-L1, a protein known to be highly expressed in the most aggressive and lethal tumors. Does this sound like a good idea?

With respect to CTLA4-Ig, this is a cell-bound version of a drug that has been approved as an anti-transplantation rejection drug called Belatacept (Nulojix), made by Bristol-Myers-Squibb. Since this is a cell-bound version of this protein, it will almost certainly not have the systemic effects of Belatacept, and if the cells manage to release a certain amount of soluble CTLA4-Ig, it is likely to be very little and have no biological effect.

Therefore, this strategy, while interesting, does come with its own share of risks and caveats.

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).