Edited by Robert D. Schreiber, Washington University School of Medicine in St. Louis, St. Louis, MO, and accepted by the Editorial Board October 29, 2011 (received for review June 25, 2011)
One of the main challenges in cancer research is the development of vaccines that induce effective and long-lived protective immunity against tumors. Significant progress has been made in identifying members of the cancer testis antigen family as potential vaccine candidates. However, an ideal form for antigen delivery that induces robust and sustainable antigen-specific T-cell responses, and in particular of CD8+ T lymphocytes, remains to be developed. Here we report the use of a recombinant nonpathogenic clone of Trypanosoma cruzi as a vaccine vector to induce vigorous and long-term T cell-mediated immunity. The rationale for using the highly attenuated T. cruzi clone was (i) the ability of the parasite to persist in host tissues and therefore to induce a long-term antigen-specific immune response; (ii) the existence of intrinsic parasite agonists for Toll-like receptors and consequent induction of highly polarized T helper cell type 1 responses; and (iii) the parasite replication in the host cell cytoplasm, leading to direct antigen presentation through the endogenous pathway and consequent induction of antigen-specific CD8+ T cells. Importantly, we found that parasites expressing a cancer testis antigen (NY-ESO-1) were able to elicit human antigen-specific T-cell responses in vitro and solid protection against melanoma in a mouse model. Furthermore, in a therapeutic protocol, the parasites expressing NY-ESO-1 delayed the rate of tumor development in mice. We conclude that the T. cruzi vector is highly efficient in inducing T cell-mediated immunity and protection against cancer cells. More broadly, this strategy could be used to elicit a long-term T cell-mediated immunity and used for prophylaxis or therapy of chronic infectious diseases.
Author contributions: C.J., S.M.R.T., F.G.R., W.D.D., S.G., L.J.O., and R.T.G. designed research; C.J., L.I.S., B.G.-F., F.G.R., and A.A.J. performed research; W.D.D., E.C., and G.R. contributed new reagents/analytic tools; C.J., S.G., and R.T.G. analyzed data; and C.J. and R.T.G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. R.D.S. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1110030108/-/DCSupplemental.
