Complete protection against melanoma in absence of autoimmune depigmentation after rejection of melanoma cells expressing α(1,3)galactosyl epitopes

The major barrier for xenotransplantation in humans is the presence of alpha(1-3) Galactosyl epitopes (alpha Gal) in xenogeneic tissue and the vast quantities of natural antibodies (Ab) produced by humans against this epitope. The binding of anti-alpha Gal Ab to cells expressing alpha Gal triggers a complement-mediated hyperacute rejection of target cells. The hyperacute rejection of whole cancer cells, modified to express alpha Gal epitopes, could be exploited as a new cancer vaccine to treat human cancers. We tested this hypothesis in alpha Galactosyltransferase knockout (alpha GT KO) mice which, like humans, do not express alpha Gal on their cell surfaces and can produce anti-alpha Gal Ab. Forty-five percent of mice with preexisting anti-alpha Gal Ab rejected alpha Gal positive melanoma cells (B16 alpha Gal). These mice remained tumor-free for more than 90 days. The majority of control mice injected with B16Null, alpha Gal negative cells succumbed to melanoma. The rejection of B16 alpha Gal induced strong long-lasting antitumor immunity against B16Null measured by the expansion of cytotoxic T lymphocytes. In addition, mice rejecting B16 alpha Gal 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 alpha Gal positive melanoma cells can efficiently boost the immune response to other tumor associated antigens present in alpha Gal negative melanoma cells. This study supports the concept of a novel anticancer vaccine to treat human malignancies.