Seaweed sugar could improve efficacy of immunotherapy in melanoma
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Although immunotherapies have been a game-changer in cancer treatment, they do not work for all patients.
Some studies have explored tumor-infiltrating lymphocytes (TILs) as a means to improve responses. TILs are immune cells that identify and attack cancer cells, but they are often either in short supply or are unable to mount a strong enough response to achieve long tumor suppression.
To address these limitations, cancer biologist Eric Lau, PhD, and colleagues at Moffitt Cancer Center have discovered a natural means of increasing the quantity and antitumor activity of TILs. In a paper published in Nature Cancer, Lau and his team characterized how L-fucose, a nontoxic plant sugar found in red and brown seaweed, can increase the number and strength of TILs and improve upon the effectiveness of immunotherapy.
“It’s a very nonclassical sugar that most people don’t think about — it’s not processed in the same way a regular table sugar is processed,” Lau told Healio. “So, it’s not taken up into our cells and used as a source of energy. It’s used simply as a way to modify proteins and fine-tune their function.”
Lau spoke with Healio about what led his team to study L-fucose and how this plant sugar could inhibit metastasis of melanoma.
Healio: How did you come to study this plant sugar as a means of suppressing tumor growth?
Lau: About 10 years ago, during my postdoctoral fellowship at the Ronai Lab at Sanford Burnham Prebys in San Diego, I studied how the regulation of different genes in melanoma could drive metastatic progression. We produced a short list of genes that might affect how melanoma metastasizes.
One of the genes on our list was FUK. This is a gene that, when expressed, allows our cells to use this sugar. If you don’t have this gene expressed, your cells in theory won’t be able to use fucose at all. What we found in that early study was that expression of FUK is progressively reduced in melanoma cells as they go from primary to metastatic. It occurred to us that perhaps melanoma cells don’t want fucose around, or that maybe using less of it helps them become more invasive. So, we did an early study and found that if you put fucose on melanoma cells, they slow down.
We thought maybe that was how the sugar was working, because we’d seen that if you give mice melanoma and then feed them fucose to raise the base level of sugar in the tumors, the tumors do get smaller. That study left us with one very interesting observation — when you cut those tumors open, the ones from the mice that consumed fucose had more immune cells. That study was done in 2015.
When I moved to Moffitt, I thought maybe the sugar was doing more than just slowing the cells down — maybe it is triggering an immune response. So, we spent the past 7 years trying to figure this out, and we found that the sugar modifies a protein on the melanoma cells that triggers this potent, T-cell-mediated immune response that helps suppress the tumors.
Healio: Have you studied this in human patients?
Lau: That is the next step — we would really love to get this sugar into clinical trials. We have gone back retrospectively and looked at how this sugar might play out in humans by studying tumor samples and biopsies. We evaluate them using tumor microarray. We had a slide that was spotted with hundreds of melanoma tumor biopsies from patients of all different disease stages, ages, sex, mutational backgrounds and more. As researchers, we’re blinded to the clinical status of these samples when we stain them, but we stained them to look at the levels of sugar within each tumor. We can also stain for the number of immune cells in these tumors.
What we found initially is that there is, indeed, a correlation between tumors with more sugar and an increased number of T cells. That was our first indication that this was probably going to play out similarly in humans. In the earlier study, we also looked at the correlation between the level of sugar in the tumors and clinical outcomes. That analysis revealed that the more sugar you have in the tumor, the better patients fare.
Part of the reason our study has taken so long is that we actually had 12 full-blown mouse models, almost 800 mice in total. We wanted to make sure that what we were seeing was real, so we built mouse model on top of mouse model so we could dig deep mechanistically and see how this was working.
We found that when the mice take up the sugar and it gets into the melanoma cells, it activates the specific immune protein that triggers an immune response. We have been able to prove in this paper that the T cells themselves will take up some of that sugar. When the sugar enters the T cells, it alters their biology and signaling and changes the way they work. The T cells take on what is called a memory phenotype, meaning they are going to stick around to help the other immune cells remember to attack the tumor if it should recur. We have studies planned to figure out if this sugar does help with immune memory.
Healio: What is next for your research on this topic?
Lau: The immediate next step is to try to get this sugar into a clinical trial for human patients with melanoma and combine it with immune checkpoint blockade. For example, if we combine it with anti-PD-1, our mouse models would indicate that it would help immunotherapy work better. That’s something that is really needed right now, because immune checkpoint blockade works only for a subset of patients — maybe 30% to 40% on a really good day. For that subset, the disease does not come back; it’s completely wiped out. For 60% to 70%, however, it doesn’t work that well. If we can increase that rate of efficacy, it would really help.
We have already initiated conversations with one of the heads of clinical trials at Moffitt, to see exactly how to get this into a clinical trial. What makes it a bit different is that this isn’t a drug we are proposing to add to a clinical trial — it’s a natural compound. So, this is more akin to clinical trials assessing things like green tea extract or dietary supplements. The first challenge will be to find a manufacturer that has human consumption-grade or [good-manufacturing-practice]-grade fucose. We’ve started reaching out to manufacturers about partnering up with them. If they can provide the material, we can provide the knowledge and clinical support to make this happen.
For more information:
Eric Lau, PhD, can be reached at H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Room 23035, Tampa, FL 33612; email: eric.lau@moffitt.org.
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