Cancer's sweet Achilles heel

Sweetness, in the case of cancer, appears as a chain of sugar molecules attached to proteins bybeta1,4-galactosyltransferase-3, orB4GALT3According to the Cancer Genome Atlas, a high expression of this enzyme is associated with noticeably shortened survival rates in several types of immunotherapy cancers, such as neuroblastoma, cervical, and bladder cancer. However, the specific role of B4GALT3 in thetumor immune microenvironment-- orTIME-- was still unknown.

Now, a team of researchers at Kyoto University and Yokohama City University has found that B4GALT3 deficiency in mice TIME inhibits tumor growth. The study shows that a significant reduction ofglycosylation-- a type of protein modification -- on T cell surfaces correlates with increases inCD8+ immune cellsinfiltrating tumors.

"In B4GALT3 knockout or KO mice, we demonstrated the potential of manipulating glycosylation of the T cell surface as a new approach to cancer immunotherapy," says Heng Wei of Kyoto University's Graduate School of Medicine.

By purifying membrane proteins and enzymatically cleaving them to enrich糖肤, the team could identify the sites and structures ofglycans-- complex and highly branched sugar chains -- and the amount ofglycoproteins. The role of glycans has attracted much attention in studies on cancer cells, which proliferate and metastasize, depending on their interaction with their microenvironment.

The team subcutaneously transplantedweakly immunogenicandstrongly immunogenictumor cells into B4GALT3 knockout and wild-type mice, to examine for tumor cell growth. Only the knockout mice suppressed the growth of strongly immunogenic tumor cells.

In addition, the increased CD8+ T cells in knockout mice secreted anti-cancer compoundsInterferon-γandGranzyme B.

"We found that the loss of B4GALT3 caused significant fluctuations in gene expression in the immune system, a discovery which has significantly changed the direction of our next phase of research," adds coauthor Chie Naruse.

"We have gained insight into the role of glycans in cancer progression and immune response, inspiring possibilities of B4GALT3-centered cancer therapies," says team leader Masahide Asano.