The major barrier for
xenotransplantation in humans is the presence of alpha(1-3) Galactosyl
epitopes (alphaGal) in xenogeneic tissue and the vast quantities of natural
antibodies (Ab) produced by humans against this
epitope. The binding of anti-alphaGal Ab to cells expressing alphaGal triggers a
complement-mediated hyperacute rejection of target cells. The hyperacute rejection of whole
cancer cells, modified to express alphaGal
epitopes, could be exploited as a new
cancer vaccine to treat human
cancers. We tested this hypothesis in alphaGalactosyltransferase knockout (alphaGT KO) mice which, like humans, do not express alphaGal on their cell surfaces and can produce anti-alphaGal Ab. Forty-five percent of mice with preexisting anti-alphaGal Ab rejected alphaGal positive
melanoma cells (B16alphaGal). These mice remained
tumor-free for more than 90 days. The majority of control mice injected with B16Null, alphaGal negative cells succumbed to
melanoma. The rejection of B16alphaGal induced strong long-lasting antitumor immunity against B16Null measured by the expansion of cytotoxic T lymphocytes. In addition, mice rejecting B16alphaGal were protected against
melanoma since they survived a second rechallenge with B16Null. Protected mice developed antitumor immunity in the absence of autoimmune depigmentation (
vitiligo). These results show that rejection of alphaGal positive
melanoma cells can efficiently boost the immune response to other
tumor associated
antigens present in alphaGal negative
melanoma cells. This study supports the concept of a novel anticancer
vaccine to treat human
malignancies.