Moffitt Cancer Center researchers say they have identified a novel approach to increase the numbers and antitumor activities of tumor-infiltrating lymphocytes (TILs). The team of researchers demonstrated in mice how L-fucose, a nontoxic dietary plant sugar that is enriched in red and brown seaweeds, can increase TILs, promote antitumor immunity, and improve the efficacy of immunotherapy.
The study is published in Nature Cancer in a paper titled, “Fucosylation of HLA-DRB1 regulates CD4+ T cell-mediated anti-melanoma immunity and enhances immunotherapy efficacy,” and led by cancer biologist Eric Lau, PhD.
“Overall levels of L-fucose in melanoma cells decrease and how the cells use L-fucose changes during progression. However, we have found that raising L-fucose levels via dietary supplementation can suppress tumors, markedly increase TILs, and enhance the efficacy of some immunotherapies in our animal models. In humans, higher levels of L-fucose in melanomas are associated with less aggressive disease and better responses to therapy,” said Lau, who is the lead study author and assistant member of the tumor biology department at Moffitt.
In mouse experiments, the researchers observed that administration of oral L-fucose increased the levels of L-fucose in tumor cells, reduced tumor growth, and increased the total levels of TILs.
“When one thinks of sugar, one often thinks of glucose or sucrose—common table sugars that our cells use for energy. Unlike those sugars, L-fucose is used by our cells not for energy but to decorate proteins to fine-tune their behavior and activity. We found that the addition of L-fucose onto the protein HLA-DRB1 causes it to be localized to the surface of melanoma cells, which triggers CD4+T cell-mediated antitumor immune cell activity,” explained Lau.
Lau’s team also found that L-fucose alters the biology and behavior of CD4+T and other immune cells, suggesting that this sugar might be used to modulate immune function. “So, we took our work one step further and discovered that oral L-fucose also enhances activity of immunotherapy drugs in some of our melanoma models.”
Next, the researchers looked at tumors from three independent groups of patients from three cancer centers to assess whether L-fucose levels and L-fucose-decorated HLA-DRB1 might reflect patient responsiveness to the immunotherapeutic agent anti-PD1. They found that patients who responded well to anti-PD1 therapy tended to have higher levels of both in their tumors, suggesting that these may be useful as potential biomarkers to predict responsiveness to immunotherapy.
“Our findings identify and delineate a molecular mechanism by which L-fucose regulates an important interface between melanoma and immune cells. This mechanism can be therapeutically leveraged by simply feeding L-fucose, which suggests a provocative and almost counterintuitive possibility: using sugar to fight cancer,” Lau said.
The researchers hope to translate their preclinical findings to help patients more directly as well as determine how much L-fucose can enhance immunotherapies, starting with a small clinical trial of melanoma patients.