Natural cytotoxic anti-tumor antibodies against NeuGcGM3 in healthy donors (127.4)

Abstract

N-glycolylated (NeuGc) gangliosides are not naturally expressed in normal human tissues but are overexpressed in several tumors and have immunosuppressive capacity, contributing to cancer progression. The present work shows the existence of a natural antibody response against NeuGcGM3 in healthy donors. 64 of the 100 donors tested had antibodies that specifically recognized NeuGcGM3 and killed tumor cells expressing the antigen by a complement mediated mechanism. Interestingly, even after complement inactivation 17% of the positive sera showed a direct cytotoxic effect on the tumor cells. This cytotoxicity was dependent on the presence of the antigen on the tumor cells and resembles an oncotic necrosis kind of cell death. The levels of anti-NeuGcGM3 antibodies in the sera of healthy donors and the percentage of donors with this natural immunity decreases with age. Furthermore we could only detect this reactivity in the sera of 5 from 51 lung cancer patients that matched in sex and age the assessed healthy donors. Non-small cell lung cancer patients vaccinated with an idiotypic antibody that mimics NeuGcGM3 elicited specific anti-tumor cytotoxic antibodies and showed longer survival times than non-responder patients. These results suggest the existence of natural antibodies against NeuGcGM3, with anti-tumor immune surveillance functions, that can be boosted in cancer patients, reinforcing the importance of N-glycolylated ganglioside as anti-tumor targets.