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Fuel for the Fight: How Cancer Metabolism Impacts the Immune System, with Dr. Greg Delgoffe

03 de marzo de 2021

Earlier this year, Greg M. Delgoffe, Ph.D., of the University of Pittsburgh School of Medicine, was named a Cancer Research Institute (CRI) Lloyd J. Old STAR, a program honoring the “Father of Modern Tumor Immunology” who served as CRI’s founding scientific and medical director. STARs (Scientists Taking Risks) receive $1.25 million over five years to implement their potentially transformative research ideas.

As an associate professor in UPitt’s Department of Immunology, Delgoffe is exploring how metabolism influences the immune system in the context of cancer and how it affects patient responses to immunotherapy. We spoke with him recently to learn more about his work and the impact of his CRI Lloyd J. Old STAR grant.

Arthur N. Brodsky, Ph.D.:

Tumor growth relies on constant division by cancer cells. Creating all these new cells takes a lot of resources and energy, and tumors often have abnormal metabolic activity to fuel this process. This was discovered a while ago, but it was only recently that we started to appreciate how this abnormal metabolic activity impacts the tumor environment and the immune cells there.

Greg Delgoffe, Ph.D.Greg M. Delgoffe, Ph.D.:

Yeah, we’ve known about deregulated metabolism of tumor cells for over a century, dating back to the German scientist Dr. Otto Warburg, who won a Nobel Prize in 1931 for identifying the metabolic pathways of cancer cells.

That knowledge is not new, but what we now know is that tumors’ deregulated energetics don’t just affect the cancer cells. They also change their surroundings, what we call the tumor microenvironment or TME. The ravenous appetite of cancer cells drains that environment of essential nutrients like glucose and oxygen, and causes a build-up of toxic byproducts that inhibit healthy cells.

Our body's own defenses, the killer T cells that we want to guard us, are being sent into that nutrient-poor “desert” environment and are starved and become dysfunctional. The immune checkpoints that we know and love in cancer immunology—like the PD-1/PD-L1 and CTLA-4 pathways—also play a role in exhausting T cells, but there’s also a primordial suppressive signal coming from the lack of fuel. Right now, immunotherapy is focused on molecular accelerators and brakes, but none of it matters if there’s no fuel in the T cell’s tank.

Arthur N. Brodsky, Ph.D.:

What role does cancer metabolism play in patient responses to immunotherapy? Can we use that information to guide treatment decisions?

Greg M. Delgoffe, Ph.D.:

Yeah, it’s an exciting opportunity to translate basic science into something that might make a difference for cancer patients. Over the past few years my lab has been collaborating with the University of Pittsburgh’s clinical experts to explore what we can measure from a patient's tumor that might tell us something about the status of the metabolic landscape. We aim to use this information to identify biomarkers that can improve doctors’ decision making, especially with respect to immunotherapy.

Cancer metabolism is already accounted for in oncology, actually. Patients generally get PET (positron emission tomography) scans, which are metabolic readouts. They visualize tissues according to how much glucose they use. Tumors usually consume a lot of glucose, so they stand out compared to normal tissues.

But that’s only scratching the surface. Not too long ago, we found that tumors that were especially hungry and had low oxygen levels were less likely to respond to checkpoint immunotherapy. In January, our Nature Immunology paper revealed how oxygen deprivation drives T cells to dysfunction. When we persistently stimulated T cells in a low oxygen environment, their mitochondria (organelles that produce most of the energy needed for cellular activity) became stressed and produced a lot of damaging molecules known as reactive oxygen species or free radicals. The T cells quickly became exhausted unless we knocked out their ability to produce these free radicals, which we found could protect them.

So, there’s a clear link between metabolic and immune signaling pathways, and by managing metabolic stress we might be able to improve the functionality of T cells. That’s the goal of my CRI STAR project: to understand what happens to T cells when they experience these negative metabolic conditions. Not just the loss of an essential nutrient, but also the toxic landscape that's produced in this vacuum of metabolic deprivation.

Delgoffe Lab at the University of Pittsburgh
Delgoffe Lab at the University of Pittsburgh. Courtesy of Greg Delgoffe.

Arthur N. Brodsky, Ph.D.:

We know that the toxic tumor landscape is detrimental to the cancer-killing T cells, but how does it affect other immune cells?

Greg M. Delgoffe, Ph.D.:

For as long as I’ve had my own lab, I’ve been looking at how regulatory T cells, or Tregs, thrive in this environment. These immune cells can protect tumors by suppressing immune responses. In another just-published paper in Nature, we found that to do so Tregs use lactate, a byproduct of tumors metabolizing glucose. Others have shown that lactate can also reprogram immune cells called macrophages and make them more tumor-friendly. Thus, by hogging the glucose, tumors steal fuel from the anti-cancer T cells and provide lactate to support the pro-cancer immune cells.

We’re starting to appreciate that it's less about the identity of the cell and more about its metabolic program that drives its function, which makes sense if you think about it. Metabolism is how cells do their work, so it makes sense that cells that share the same function will share the same fuel.

And to be clear, in many ways, this lactate consumption is normal behavior. A lot of cells use lactate as a fuel source because it's abundant, it's easy to use as a burnable fuel, especially in places—like the brain, damaged muscle, and the gut—where you may want to temper some immune activity. We think that this is a mechanism by which immune activity is guarded in certain organs and tissues are protected against excessive immune responses.

But in cancer it backfires, so we want to understand the mechanisms behind it, so hopefully we can develop ways to overcome it. The key idea is that it's not just a loss of good stuff, the glucose. It's also the metabolic byproducts—the lactate and other small carbon energy sources—that shift the overall immune balance in the tumor microenvironment.

Arthur N. Brodsky, Ph.D.:

How might your work enable us to improve care for people with cancer?

Greg M. Delgoffe, Ph.D.:

It’s fun to do science. I love to learn, but it’s always important to have logical, practical next steps as far as how to take what we’re learning in the lab and use it to help in the clinic. How can we use that information to improve immunotherapy for cancer?

Quite simply, we don’t have the answer yet. We have to do our basic research, which is the foundation of the whole translational process. This is embodied in the 2018 Nobel Prize for Medicine or Physiology that was awarded to Drs. James Allison and Tasuku Honjo for their groundbreaking work in checkpoint immunotherapy. These two scientists were just trying to figure out how T cells worked and revealed the brakes that, when blocked, could promote T cell responses against cancer.

Now, for those of us interested in the tumor microenvironment, we need to know more about how those altered conditions influence T cell activity and fate. We still don’t have a great understanding of how T cells behave in the very different circumstances found within tumors compared to normal tissues. If we know what the immune system needs, we might be able to identify actionable strategies to guide the use of current immunotherapies.

So, what are some ways we might tip the balance in favor of the immune system? If the tumor microenvironment is pro-tumor, is there any straightforward way to temper the tumor’s appetite?

It turns out the answer is yes. We were surprised that it didn’t take much to refuel the anti-tumor immune response, given that many drugs that alter metabolism exist for other diseases. Of note was the type 2 diabetes drug metformin. When given to mice, it created a more permissive environment for T cells within tumors and enabled them to respond to checkpoint immunotherapy better. We think this is a key aspect of a metabolic therapy; it doesn’t have to kill the cancer cell on its own, but rather just tip the balance in favor of the anti-tumor immune response.

Since then we’ve launched several clinical trials exploring this approach, which we hope will be successful. Overall, we hope we can move the needle a little bit by revealing important insights that can define the next target that we go after. I think it’s going to be really exciting.

Delgoffe Lab Christmas Party in 2018
Delgoffe Lab Christmas Party in 2018. Courtesy of Greg Delgoffe.

Arthur N. Brodsky, Ph.D.:

How important is the CRI STAR funding for your work, especially with the long-term nature of the grant and the flexibility it provides?

Greg M. Delgoffe, Ph.D.:

I've been affiliated with CRI for a long time, before immunotherapy was successful at all. As a graduate student, I'd go up to the CRI scientific meeting in New York, where a small group of people talked T cells and cancer. CRI has always been a dominant force in cancer immunology, but to see the growth and expansion and now the clinical successes backing it up is amazing.

I'm very honored that an organization like CRI, which has kept the cancer immunotherapy candle lit for decades, is supporting the risk-taking nature of my lab’s approaches. A lot of times traditional funding is risk-averse, and you don't actually get the opportunity to develop something really exciting.

The CRI STAR funding provides the flexibility that allows us to follow the data, to find the key insights that we can leverage, and then try to translate those basic discoveries. All the successes in cancer immunology were about people driving and going after something that they were excited about, even though it was an unconventional approach and not considered a safe bet.

I'm very passionate about this work. Energizing our immune system and finding ways to take advantage of that to benefit patients in the clinic is something we’re really keen on developing.

Five years from now, I hope that we have a more complete understanding of why T cells can fail in cancer. When we understand what dysfunctional T cell environments looks like, then maybe we can intervene in a way that reinvigorates them and makes them more effective against cancer.

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