Stem Cell Vaccination Against Cancer: Fighting Fire With Fire?

A recent report1Li Y Zeng H Xu R-H Liu B Li Z Vaccination with human pluripotent stem cells generates a broad spectrum of immunological and clinical response against colon cancer.Stem Cells. 2009; (e-pub ahead of print 8 October 2009)Google Scholar suggests yet another application for embryonic stem (ES) cell technology: using such cells to immunize against cancer. However, before this novel strategy can prove useful, several issues need to be resolved. ES cells derived from preimplantation embryos2Thomson JA Itskovitz-Eldor J Shapiro SS Waknitz MA Swiergiel JJ Marshall VS et al.Embryonic stem cell lines derived from human blastocysts.Science. 1998; 282: 1145-1147Crossref PubMed Scopus (12274) Google Scholar and induced pluripotent stem (iPS) cells obtained by transient overexpression of specific transcription factors in somatic cells3Takahashi K Tanabe K Ohnuki M Narita M Ichisaka T Tomoda K et al.Induction of pluripotent stem cells from adult human fibroblasts by defined factors.Cell. 2007; 131: 861-872Abstract Full Text Full Text PDF PubMed Scopus (14962) Google Scholar,4Yu J Vodyanik MA He P Slukvin II Thomson JA Human embryonic stem cells reprogram myeloid precursors following cell-cell fusion.Stem Cells. 2006; 24: 168-176Crossref PubMed Scopus (110) Google Scholar,5Jaenisch R Young R Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming.Cell. 2008; 132: 567-582Abstract Full Text Full Text PDF PubMed Scopus (1115) Google Scholar are frequently said to hold the potential to revolutionize biomedical research by providing new substrates for biological studies designed to understand human diseases, by offering cellular transplantation and replacement therapies, and by serving as a platform for pioneering drug development and screening efforts. However, as the history of biomedical research has made clear, the most triumphant breakthroughs have often emerged from areas initially not considered promising by most researchers. Could it be, then, that this recent report1Li Y Zeng H Xu R-H Liu B Li Z Vaccination with human pluripotent stem cells generates a broad spectrum of immunological and clinical response against colon cancer.Stem Cells. 2009; (e-pub ahead of print 8 October 2009)Google Scholar by Bei Liu, Zihai Li, and others from the University of Connecticut Stem Cell Institute represents such a contemporarily disparaged yet potentially promising application of stem cell technology? The jury is still out on this question; however, it is worth carefully examining the experiments presented by these authors and contemplating their meaning. One of the most auspicious, yet challenging, avenues for combating malignancies is to enlist the immune system to come to the defense of the patient. However, myriad components of the immune system interact in extraordinarily complex ways with active or dormant neoplastic cells, an interaction matrix that is incompletely understood at best. Nevertheless, it is apparent that the emergence of disease must be at least partly the consequence of both a failure of the immune system to respond adequately and the evolution of escape mechanisms by malignant cells. In their article,1Li Y Zeng H Xu R-H Liu B Li Z Vaccination with human pluripotent stem cells generates a broad spectrum of immunological and clinical response against colon cancer.Stem Cells. 2009; (e-pub ahead of print 8 October 2009)Google Scholar Li et al. reason that exposure of the immune system to novel tumor-associated antigens might boost an otherwise inadequate immune response into an effective antitumor action. What distinguishes the study is the source of these tumor-associated antigens: human ES and iPS cells. Specifically, the study investigated whether vaccination of mice with human ES or iPS cell lines would trigger an enhanced immunological response against shared antigens expressed by the primitive normal cells and the colon carcinoma cell line CT26—so-called oncofetal antigens. The authors report that vaccination of mice with the human ES cell line H9 induced both strong cellular and humoral immune responses against CT26 colon carcinoma that was manifested as a retardation of proliferation after injection of the cells into the experimental animal. On a more mechanistic level, they found that the protection correlated with an expansion of tumor-responsive and interferon-γ-producing cells and a profound loss of CD11b+Gr-1+ myeloid-derived suppressor cells in the spleen. Importantly, they found no evidence of any significant autoimmunity. Finally, the authors compared the immunogenicity of their human ES cell line against CT26 colon carcinomas with that of a newly established iPS cell line. Curiously, they obtained evidence that suggests that the iPS cell line was inferior to the human ES cell line in conferring tumor protection. By way of explanation, they proposed that oncofetal antigens were differentially expressed in human ES and iPS cells. Three aspects of this study seem to deserve particular attention. The first is the concept of tumor stem cells. The authors reason that if the cancer stem cell concept is valid, then immunization with stem cells should prove valuable. However, it is possible to argue that human ES cells as a stem cell entity are defined merely on the basis of functional characteristics observed in vitro6Smith AG Embryo-derived stem cells: of mice and men.Annu Rev Cell Dev Biol. 2001; 17: 435-462Crossref PubMed Scopus (1038) Google Scholar and that they are not likely to represent authentic stem cells found during embryogenesis or in adult somatic tissues. If this is the case, it would be difficult to accept at face value claims that the observed protective effect was attributable to specific immunogenicity against tumor stem cells. Second, the authors propose that the particularly primitive nature of human ES cells (given their embryonic origin) could form the basis for the specific effects against CT26. Although this may be partially true, for the most part the data presented do not directly address this. Instead, it seems that aberrant (and indeterminate) exposure to human antigens, regardless of the origin of the cell line, was critically responsible for the observed effects. Although they will no doubt be laborious, experimental strategies aimed at discerning the immunospecificity of the effects of human ES cells will be necessary to resolve this question. Finally, the apparent difference between iPS and ES cells clearly deserves attention; however, future studies must address this variability as more than a mere formality. The evidence that human ES and iPS cells are different in any substantial way is, at best, preliminary. Until the authors perform the requisite well-controlled experiments, which are not trivial, it would be easy to mistake inter–cell line variations for intrinsic biological differences. There is a certain irony in the fact that human ES cells, which themselves possess many features of neoplastic cells6Smith AG Embryo-derived stem cells: of mice and men.Annu Rev Cell Dev Biol. 2001; 17: 435-462Crossref PubMed Scopus (1038) Google Scholar,7Damjanov I Solter D Experimental teratoma.Curr Top Pathol. 1974; 59: 69-130Crossref PubMed Scopus (128) Google Scholar,8Sperger JM Chen X Draper JS Antosiewicz JE Chon CH Jones SB et al.Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors.Proc Natl Acad Sci U S A. 2003; 100: 13350-13355Crossref PubMed Scopus (570) Google Scholar—including sustained telomerase activity, formation of tumors after injection into mice, and infinite growth—would be exploited against cancer. By analogy, it is like fighting fire with fire. However, given the great uncertainty surrounding the nature of human ES cells, and thus the parameters that confer the ability to interact with the immune system, one must be cautious lest the positive analogy be replaced by the image of an 8-year-old boy playing with matches. It is an obligatory exercise to dissect the specific effects of pluripotent cells and to determine how beneficial and safe they are relative to existing immunotherapeutic concepts. On balance, it is rewarding to see the potential spectrum of the application of human pluripotent stem cells growing far beyond what most of us have envisioned. This and other studies clearly indicate that the field of ES and iPS cells has entered a new, more mature era. As in most endeavors, timing is critical. But it is rewarding to see that the political climate with respect to science in general, and ES cells in particular, seems to be moving in a more favorable direction worldwide, especially in the United States. Scientific discoveries as well as progress on the political–ethical front will guarantee that stem cell research will have a profound and positive impact on the future of biomedical research and therapy.