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Exploring the Potential of Natural Killer Cells with Dr. Oscar Aguilar

June 23, 2020

While T cells remain central to the most effective cancer immunotherapy approaches to date, there are several other immune cells within our bodies that are capable of recognizing and attacking cancer cells—and may be key to enabling us to conquer all forms of cancer in humans.

Dr. Oscar Aguilar of UCSFOne example is natural killer cells, or NK cells, which share a common lineage with T cells. There is still much to learn about the molecular mechanisms underlying NK cell activity though, so Oscar A. Aguilar, Ph.D., a CRI postdoctoral fellow at the University of California, San Francisco (UCSF), is working to characterize their biology more deeply. Working with renowned NK cell expert Lewis L. Lanier, Ph.D., who is also a member of the CRI Scientific Advisory Council, Dr. Aguilar hopes to determine how we might use these immune cells to create more effective immunotherapies against cancer.

Recently, we spoke with Dr. Aguilar to learn more about his progress.

Arthur N. Brodsky, Ph.D.:

What are natural killer cells and what role do they play in the immune system?

Oscar A. Aguilar, Ph.D.:

Natural killer (NK) cells are part of the innate branch of the immune system. We typically think of them as sentinels that patrol our tissues and act as first responders. They look for abnormal cells, and they're able to kill these cells even if they haven’t encountered or been sensitized to them before, which means that they're effective initial responders as soon as an assault happens. For that reason, they're very efficient at killing any cells that have been virally infected or become mutated through cancerous transformation.

Arthur N. Brodsky, Ph.D.:

One way that natural killer cells can recognize diseased cells is through a process called antibody-dependent cellular cytotoxicity, or ADCC. What are antibodies, and what does this process involve?

Oscar A. Aguilar, Ph.D.:

Antibodies are proteins produced by other immune cells called B cells. They can be customized to bind to a wide variety of threats, including diseased cells, bacteria, and viruses—and then mark them for destruction. One of the first things we realized about natural killer cells is that they are effective at killing cells that have been coated by antibodies, which let the NK cells know that they need to be eliminated. So, antibody-dependent cellular cytotoxicity, or ADCC, is the name of this process, whereby certain cells of the immune system, like NK cells, can kill anything that has been coated with antibodies because it usually means they are foreign or otherwise dangerous.

A natural killer cell
A natural killer cell

Arthur N. Brodsky, Ph.D.:

One crucial component in ADCC is the CD16 receptor, which is found on the surface of NK cells and enables them to bind to the antibodies that are attached to threats. Learning more about the biology of CD16 might enable us to develop NK cell-based immunotherapies against cancer, but so far it’s been difficult to investigate using animal models, specifically mice. Fortunately, a big focus of your research is to help us overcome this hurdle. So, can you explain why CD16 has been so hard to study in the lab, and how you are working to address it?

Oscar A. Aguilar, Ph.D.:

Definitely. CD16 was one of the first receptors that was discovered in NK cells, and it binds the “back ends” of antibodies, known as the Fc region. There has been quite a bit of interest in studying these types of receptors—known as Fc-gamma receptors—in humans. However, what we’ve witnessed and what other biologists have seen in many different processes, is that there are striking differences between mouse NK cells and human NK cells. These differences extend to the CD16 receptor.

Human NK cells are very effective at clearing antibody-coated cells, but mouse NK cells don’t appear to have the same ability. I'm trying to piece out why that is and identify some of the molecular differences that are responsible. This may show us how we can amplify CD16’s protective capability.

One of the big advantages of doing lab research with mice is that we can do much more thorough analyses of what's going on at the molecular level. Obviously, the goal isn’t to cure cancer in mice, but by gaining a deeper understanding of CD16’s mechanisms, we can use those insights to potentially develop improved treatments for humans with cancer.

Arthur N. Brodsky, Ph.D.:

Aside from stimulating NK cells’ killing capabilities, you're also looking at how CD16 influences the proliferation and long-term immune memory of NK cells. So, first, what is immune memory? And second, why are proliferation and memory important in the context of potential NK cell-based immunotherapies?

Oscar A. Aguilar, Ph.D.:

That's a very good question. Immune memory is the ability of immune cells to “remember” past battles and threats. This commonly occurs with viruses and bacteria but can also happen with cancer.

For a long time the central dogma held that only adaptive immune cells—like B and T cells—have this ability. We now know that NK cells also have this ability. And this has been best demonstrated in the control of viruses, in particular one called cytomegalovirus (CMV), which can be deadly for patients who have received a bone marrow transplant and have decreased immune functioning.

CMV is common in humans, but most have asymptomatic infections without any severe effects. And the reason why that is, we think, is because there has been a long history of co-evolution between us and this virus, in particular with respect to the molecules at the interface of this virus and our immune systems. So, because of this tight co-evolution that's been taking place, some NK cells have the ability to directly detect CMV proteins.

Once CMV is detected, NK cells undergo this prolific expansion and they're able to generate these memory NK cells that are more effective at clearing secondary infection. So, now that we know we can generate memory NK cells in response to CMV infection, we are exploring if we can get NK cells to “remember” other threats, such as other viruses and cancer. If so, our next step would be to see if we can make NK cells better at killing cancer cells, too.

Natural killer cells (blue, purple) attacking a liver cancer cell line (pink). Photo by Steve Gschmeissner / Science Photo Library.
Natural killer cells (blue, purple) attacking a liver cancer cell line (pink). Photo by Steve Gschmeissner / Science Photo Library

Arthur N. Brodsky, Ph.D.:

So, and how might the insights you uncover help us to develop more effective immunotherapies for patients with cancer?

Oscar A. Aguilar, Ph.D.:

We already know that NK cells are very effective at killing or controlling leukemias, types of blood cancers. But they’re not thought to be great at controlling solid cancers for a variety of reasons, including that solid tumors are usually much more heterogeneous (have different gene expression throughout the tumor) and often have a tumor microenvironment that can suppress immune activity.

My hope is that by advancing our understanding of NK cells, we can make them more effective at controlling these other types of cancers because, in theory, they're equipped to target pretty much any type of cancer. Due to their capabilities, NK cells are increasingly being considered promising choice for cell therapies. To maximize their potential, though, it’s essential that we understand how best to activate them in order to specifically clear cancers and viruses.

So, I’m approaching that goal from the angle of how we can harness the power of the adaptive immune system, which involves antibodies and T cells and B cells, to fortify the innate immune system’s defenses, especially NK cells.

Arthur N. Brodsky, Ph.D.:

How important has CRI’s support been for your pursuit of this work, financially as well as being part of the CRI scientific community?

Oscar A. Aguilar, Ph.D.:

CRI's support has truly been priceless. Funding from CRI has allowed me to take leaps of faith—or I guess I should say educated guesses—with my research. It really makes me feel like I’m playing for the right team. This organization certainly has the right approach to tackling these ambitious goals. Maybe it's because I'm a basic immunologist, but whenever I go to meetings, it seems like the hot topics are always the translational science coming from scientists who are at the front lines treating patients. But CRI’s support and encouragement—as well as that of the other scientists in the CRI community—really reassures me that my contribution to the big picture is important in reaching our goals. These connections and experiences are truly amazing, and something for which I’m extremely grateful.

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