Cough syrups are often "yucky and potent," which seems to imply that any sweetening ingredients may weaken the effectiveness of the medicine. In the case of cancer, that sweetness is a chain of sugar molecules attached to proteins by the enzyme beta 1,4-galactosyltransferase-3 (or B4GALT3). Researchers at Kyoto University and Yokohama City University found that a lack of B4GALT3 in mice resulted in reduced tumor growth, highlighting a potential new approach to cancer immunotherapy. Research shows that a lack of B4GALT3 in mice slows tumor growth and alters immune responses, suggesting new cancer treatment strategies.
According to the Cancer Genome Atlas, high expression of this enzyme is associated with significantly shorter survival rates in patients with several immunotherapy cancers, such as neuroblastoma, cervical cancer, and bladder cancer. However, the specific role of B4GALT3 in the tumor immune microenvironment (or TIME) remains unknown.
Weakly and strongly immunogenic tumor cells were transplanted subcutaneously into B4GALT3 knockout and wild-type mice. The growth of tumor cells in gene knockout mice was significantly inhibited. Source: KyotoUJakeTobiyama/HengWei
Breakthrough research on B4GALT3 and cancer
Now, a research team from Kyoto University and Yokohama City University has discovered that mice lacking B4GALT3 suppress tumor growth. Studies have shown that a significant reduction in T cell surface glycosylation, a protein modification, correlates with an increase in tumor-infiltrating CD8+ immune cells.
"In B4GALT3 knockout or KO mice, we demonstrated the potential of manipulating T cell surface glycosylation as a new approach to cancer immunotherapy," said Heng Wei of Kyoto University Graduate School of Medicine.
By purifying membrane proteins and enzymatically digesting them to enrich for glycopeptides, the team could determine the location and structure of glycans (complex, highly branched sugar chains) as well as the number of glycoproteins. The role of glycans has attracted much attention in research on cancer cells, whose proliferation and metastasis depend on their interactions with the microenvironment.
Experimental results and future directions
The research team transplanted weakly immunogenic and strongly immunogenic tumor cells into B4GALT3 knockout mice and wild-type mice respectively to detect the growth of tumor cells. Only the knockout mice inhibited the growth of highly immunogenic tumor cells.
In addition, the increased CD8+ T cells in the knockout mice can secrete the anti-cancer compounds interferon-γ and GranzymeB.
"We found that loss of B4GALT3 causes significant fluctuations in immune system gene expression, a finding that dramatically changes the direction of our next phase of research," added co-author Chie Naruse.
"Our deep understanding of the role of glycans in cancer progression and immune response has inspired the possibility of B4GALT3-centered cancer therapies," said team leader Masahide Asano.
Reference: "Beta-1,4-galactosyltransferase-3 deficiency suppresses immunogenic tumors in mice" by Heng Wei, Chie Naruse, Daisuke Takakura, Kazushi Sugihara, Xuchi Pan, Aki Ikeda, Nana Kawasaki, and Masahide Asano. "Beta-1,4-galactosyltransferase-3deficiencysuppressesthegrowthofimmunogenictumorsinmice", September 18, 2023, "Frontiers in Immunology".
DOI:10.3389/fimmu.2023.1272537