Interference with O‐glycosylation in RMA lymphoma cells leads to a reduced in vivo growth of the tumor

Abstract

Carbohydrate processing in cancer cells can influence the growth, metastatic potential, vascularization and immune recognition of such cells. Interference with N‐glycosylation has been shown both to reduce the membrane expression of MHC class I and to increase the in vitro sensitivity of tumor cells to NK cell killing. We investigated the effect of O‐glycosylation inhibition on the in vivo growth, phenotype and NK sensitivity of RMA lymphoma cells using benzyl N‐acetyl‐α‐D‐galactosamide (BAG). BAG‐treated cells were found to have a strongly reduced local growth potential in vivo. However, inhibition of O‐glycosylation caused this effect without any significant downregulation of MHC‐I and increase in sensitivity to NK killing as seen after inhibition of N‐glycosylation using Castanospermine. BAG treatment of RMA cells resulted in the removal of larger O‐linked glycans and a high expression of the T‐antigen (GalGalNAc), a target for natural antibodies (NAs) induced by the gastrointestinal bacterial flora. Whether the loss of larger O‐linked glycans, and associated functions, or of biological effects of NA contributed to the antitumor effect remains to be established. The results support the idea that inhibitors of O‐ as well as N‐linked glycosylation may be useful for the treatment of cancer, given that they can be specifically targeted to the tumor tissue. © 2006 Wiley‐Liss, Inc.

Polysialic Acid, a Glycan with Highly Restricted Expression, Is Found on Human and Murine Leukocytes and Modulates Immune Responses

“…RMA-S cells, which have reduced MHC class I expression, are sensitive to NK killing, while the parental RMA cells form tumors in wild-type animals (24). In initial experiments, RMA-S cells formed tumor masses in NK cell-depleted wildtype animals (25), but not wild-type or ST8Sia IV Ϫ/Ϫ mice.…”

Tumor-Associated Glycans and Immune Surveillance

“…Swainsonine, in particular, is interesting, as it inhibits the formation of N -linked complex oligosaccharides with this inhibition correlative with enhancement with NK cell function. Consequently, inhibitors of N -, as well as O -linked glycosylation need to be expanded, because they should be useful for the treatment of cancer by effectively resetting NK functional activity by disruption of negative signals; given that inhibitors can be specifically targeted to tumor tissue [ 144 ]. More recently, it was shown that glycosylation regulates NK cell-mediated effector function through the PI3K pathway [ 132 ].…”