Complete protection against melanoma in absence of autoimmune depigmentation after rejection of melanoma cells expressing α(1,3)galactosyl epitopes
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The major barrier for xenotransplantation in humans is the presence of α(1–3) Galactosyl epitopes (αGal) in xenogeneic tissue and the vast quantities of natural antibodies (Ab) produced by humans against this epitope. The binding of anti-αGal Ab to cells expressing αGal triggers a complement-mediated hyperacute rejection of target cells. The hyperacute rejection of whole cancer cells, modified to express αGal epitopes, could be exploited as a new cancer vaccine to treat human cancers. We tested this hypothesis in αGalactosyltransferase knockout (αGT KO) mice which, like humans, do not express αGal on their cell surfaces and can produce anti-αGal Ab. Forty-five percent of mice with preexisting anti-αGal Ab rejected αGal positive melanoma cells (B16αGal). These mice remained tumor-free for more than 90 days. The majority of control mice injected with B16Null, αGal negative cells succumbed to melanoma. The rejection of B16αGal induced strong long-lasting antitumor immunity against B16Null measured by the expansion of cytotoxic T lymphocytes. In addition, mice rejecting B16αGal 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 αGal positive melanoma cells can efficiently boost the immune response to other tumor associated antigens present in αGal negative melanoma cells. This study supports the concept of a novel anticancer vaccine to treat human malignancies.
KeywordsCancer vaccine Alpha(1, 3)Galactosyl epitope Adjuvant Xenotransplant Melanoma
Rossi GR was funded by NewLink Genetics Corporation through a Research and Development Agreement. The authors would like to thank Dawn Bertrand, for her outstanding efforts and invaluable help in the management of the Animal Care Facility at the Iowa Cancer Research Foundation. The authors also would like to thank Dr Sergei Kisselev for his assistance in the FACS and Dr Mario R Mautino for his help in revising this manuscript.
- 15.Induction and measurement of cytotoxic t lymphocyte activity (2001) Current protocols in immunology Chapter 3. In: Coico R (ed) Vitro Assays for Mouse Lymphocyte Function. John Wiley& Sons, New YorkGoogle Scholar
- 35.van Elsas A, Hurwitz AA, Allison JP (1999) Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 190:355–366CrossRefPubMedGoogle Scholar
- 37.Watier H, Guillaumin JM, Piller F, Lacord M, Thibault G, Lebranchu Y, Monsigny M, Bardos P (1996) Removal of terminal alpha-galactosyl residues from xenogeneic porcine endothelial cells. Decrease in complement-mediated cytotoxicity but persistence of IgG1-mediated antibody-dependent cell-mediated cytotoxicity. Transplantation 62:105–113CrossRefPubMedGoogle Scholar