Effects of histocompatibility and host immune responses on the tumorigenicity of pluripotent stem cells

Abstract

Pluripotent stem cells hold great promises for regenerative medicine. They might become useful as a universal source for a battery of new cell replacement therapies. Among the major concerns for the clinical application of stem cell-derived grafts are the risks of immune rejection and tumor formation. Pluripotency and tumorigenicity are closely linked features of pluripotent stem cells. However, the capacity to form teratomas or other tumors is not sufficiently described by inherited features of a stem cell line or a stem cell-derived graft. The tumorigenicity always depends on the inability of the recipient to reject the tumorigenic cells. This review summarizes recent data on the tumorigenicity of pluripotent stem cells in immunodeficient, syngeneic, allogeneic, and xenogeneic hosts. The effects of immunosuppressive treatment and cell differentiation are discussed. Different immune effector mechanisms appear to be involved in the rejection of undifferentiated and differentiated cell populations. Elements of the innate immune system, such as natural killer cells and the complement system, which are active also in syngeneic recipients, appear to preferentially reject undifferentiated cells. This effect could reduce the risk of tumor formation in immunocompetent recipients. Cell differentiation apparently increases susceptibility to rejection by the adaptive immune system in allogeneic hosts. The current data suggest that the immune system of the recipient has a major impact on the outcome of pluripotent stem cell transplantation, whether it is rejection, engraftment, or tumor development. This has to be considered when the results of experimental transplantation models are interpreted and even more when translation into clinics is planned.

Fig. 1

Teratoma growth after injection of MPI-II ESCs is accelerated in SCID/beige compared to SCID and syngeneic 129Sv mice. The 1 × 10⁶ MPI-II ESCs were injected subcutaneously at day 0 into syngeneic 129Sv mice (n = 26), T and B cell-deficient SCID (n = 14) and T, B, and NK cell-deficient SCID/beige mice (n = 15). The tumor size was recorded every second day using linear calipers. A summary of the growth (mean ± standard error of the mean) until day 30 is shown, newly evaluating previously published data [61]. The comparison of tumor size in SCID and SCID/beige or 129Sv mice, respectively, indicates a significant difference at days 18, 20, 22, 28, and 30 (P < 0.05, unpaired t test)

Fig. 2

Schematic representation of factors which influence the outcome of pluripotent stem cell transplantations. Besides graft-related factors, such as pluripotency and therapeutic efficacy, host-related factors in first line immune-mediated rejection mechanisms have to be taken into consideration to understand the outcome of transplantations of pluripotent stem cells or their differentiation products. Possible outcomes include rejection, engraftment, teratoma formation, or growth of lineage-restricted tumors. Host factors presumably explain some of the variations observed with different cell types in different experimental transplantation models