Immunotherapies have improved outcomes for many cancer patients, including melanoma. But these therapies only work in a subset of patients. Numerous studies are looking at improving responses, including research focused on improving tumor-infiltrating lymphocytes (TILs). TILs are immune cells in tumors that can recognize and attack the cancer cells, but often there aren’t enough of them or they are unable to use a strong enough response to permanently suppress the growth and spread of the tumor.
Researchers at the Moffitt Cancer Center, led by cancer biologist Eric Lau, Ph.D., have found a relatively natural way to increase the number and antitumor activities of TILs. In a new article published in nature cancerLau’s team shows how L-fucose, a non-toxic plant sugar enriched in red and brown algae, can increase TILs, promote antitumor immunity and improve the effectiveness of immunotherapy.
While the sugar molecule L-fucose is found in food, it can also be made in our own cells through the breakdown and conversion of other molecules. It is important in immune and developmental processes, and abnormalities in L-fucose synthesis and utilization have been implicated in disease, including cancer.
“The total level of L-fucose in melanoma cells decreases and the way the cells use L-fucose changes during progression. However, we have found that increasing L-fucose levels through dietary supplementation can suppress tumors, significantly increase TILs, and increase the effectiveness of some immunotherapies in our animal models. In humans, higher L-fucose levels in melanoma are associated with less aggressive disease and better response to therapy,” said Lau, lead author of the study and associate member of Moffitt’s Division of Tumor Biology.
The research team aimed to determine the mechanisms underlying how L-fucose appears to increase TILs and trigger their antitumor activity. For almost seven years, they conducted a series of laboratory experiments and showed for the first time that L-fucose can regulate interactions between CD4s+T cells, a type of TIL, and melanoma cells. In mouse experiments, they found that oral L-fucose administration increased L-fucose levels in tumor cells, reduced tumor growth, and increased overall levels of TILs. Their studies found that of the many types of immune cells that comprise TILs, CD4+T cells play a critical role in mediating the increase in TILs that suppress melanoma during L-fucose treatment. Researchers identified the key molecular mechanisms contributing to L-fucose-mediated CD4+T cell antitumor activity.
“When people think of sugar, they often think of glucose or sucrose – common table sugars that our cells use for energy Behavior and Activity We found that adding L-fucose to the protein HLA-DRB1 caused it to be surface of melanoma cells, triggering CD4+T cell-mediated antitumor immune cell activity,” Lau said.
In addition to decorating proteins in tumor cells, Lau’s team also found that L-fucose alters the biology and behavior of CD4+T and other immune cells, suggesting that this sugar could be used to modulate immune function. These findings have important implications for the use of L-fucose to enhance immunotherapies currently used to treat cancer patients. “So we took our work a step further and discovered that oral L-fucose also enhances the activity of immunotherapeutic agents in some of our melanoma models.”
Next, the researchers examined tumors from three independent patient groups from three cancer centers to assess whether L-fucose levels and L-fucose-decorated HLA-DRB1 might reflect the patient’s response to the immunotherapy drug 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 could be useful as potential biomarkers to predict response to immunotherapy.
“Our results identify and describe a molecular mechanism by which L-fucose regulates an important interface between melanoma and immune cells. This mechanism can be exploited therapeutically simply by ingesting L-fucose, suggesting a provocative and almost counterintuitive possibility: using sugar to fight cancer,” Lau said.
Going forward, Lau and his team hope to translate their preclinical findings to more directly help patients and determine how much L-fucose can improve immunotherapies, starting with a small clinical trial in melanoma patients.
Her work is supported by a Miles for Moffitt Award from the National Institute of General Medical Sciences (GM061126), the National Cancer Institute (P30CA076292, K99CA172705, R00CA172705, R01CA241559), the Harry J. Lloyd Charitable Trust and the Moffitt Foundation.