Meet Dr. Amanda Lund, One of the New CRI Lloyd J. Old STARs

Earlier this year, the Cancer Research Institute (CRI) launched its ambitious Lloyd J. Old STAR Program, named in honor of the “Father of Modern Tumor Immunology,” who served as CRI’s founding scientific and medical director from 1971 to 2011.

Old’s bold vision helped us build the foundation upon which immunotherapy has achieved its current success and helped transform how we think about treating cancer.  Now, to bring cures to all patients, we’ll need to venture beyond what’s already known and push the boundaries of what’s currently possible with immunotherapy. This will require taking risks, and that’s exactly what these STARS—Scientists Taking Risks—will do.

With CRI support—each STAR will receive $1.25 million over the next 5 years—these promising STARs will be exploring high-risk, high-reward ideas with the potential to produce transformative leaps forward that will enable the field’s next great advances and bring us ever closer to a future immune to cancer.

One of these promising STARs is Amanda Lund, PhD, of the Oregon Health and Science University (OHSU) in Portland, Oregon, who has made a number of contributions that have advanced our understanding of the lymphatic system, which plays an important role in the ability of our immune system to protect us against threats.

Currently, Dr. Lund is an associate professor of cell, developmental, and cancer biology, and a member of the Knight Cancer Institute at OHSU. Previously, Dr. Lund earned a PhD from the Rensselaer Polytechnic Institute (NY), where she worked under George E. Plopper, PhD, and Jan P. Stegemann, PhD Subsequently, she was a postdoctoral fellow in the lab of Melody A. Swartz, PhD, at the Swiss Federal Institute of Technology Lausanne in Swizterland as well as a former CRI CLIP Investigator (2015-2018).

Recently, we spoke with Dr. Lund to learn more about her work and what she hopes to accomplish during the next five years as a CRI Lloyd J. Old STAR.

Arthur N. Brodsky, PhD:

Your research focuses on a part of the body known as the lymphatic system, which includes the lymph nodes. What exactly is the lymphatic system is and how does it help maintain the health of our bodies?

Amanda W. Lund, PhD:

The body has two vascular systems. The blood is probably the most well-known and plays an important role in bringing nutrients and oxygen to all of our different tissues throughout the body.

The second is the lymphatic system. It actually starts out in our peripheral tissues, away from the heart. It doesn’t have a centralized pump, like blood vessels do with the heart, but the vessels themselves pump to drive regional lymph flow. Because of this, the lymphatic system plays an important role in clearing our tissues of the excess fluid and cells that build up within them. Additionally, before these contents recirculate back into the blood, they pass through the lymph nodes, where they are scanned by immune cells to see if there are any threats that need to be addressed.

In this way, the lymph nodes serve as the epicenters of immune responses. Once the immune cells within lymph nodes sample and survey the information from the tissues, they can help orchestrate immune activity against any threats that they detect.

Because of the physical route that these vessels provide, the lymphatic system’s importance has been appreciated for a long time. The canonical view, however, had been that these vessels were simply physical pathways and nothing more.

This idea extends into cancer as well, because we know that tumor cells can use these pathways to metastasize—to move from the primary tumor to the lymph node and potentially to other, distant tissues. Once a patient has tumor cells in their lymph nodes or another organ, their survival outlook typically isn’t very good. So, this idea of lymphatic vessels as passive conduits was prevalent both in the immunology field as well as in the cancer field, but how those two linked together hasn’t really been explored in depth.

Read Dr. Lund's Article on lymphatic vessels and antitumor immunity

Arthur N. Brodsky, PhD:

Your recent work has shown that these lymphatic vessels are more than just passive conduits or highways, but that they appear to play a more active role than was previously believed, right?

Amanda W. Lund, PhD:

Yes, absolutely. First, we realized that by manipulating lymphatic vessels, we could manipulate immune responses against cancer. We found that the movement of information from the tumor and its surrounding microenvironment to the draining lymph node by lymphatic vessels was critical to determining how the immune system responded to that developing tumor. That set up this paradigm that lymphatic function might directly regulate immune activity against cancer, as opposed to just being a passive player in all of these processes.

These specialized vessels—which we call lymphatic capillaries—are a thin layer of cells that are in direct contact with the cells that are present within the tissue or tumor. We’ve come to appreciate that the vessels themselves and the cells that make up these vessels are dynamic. They respond to changes in their environment, they regulate the expression of molecules that promote cell adhesion, which is necessary for both immune cells and tumor cells to move through those vessels.

Some of our newer work has shown that the vessels can regulate how much fluid is moving through them. So lymphatic vessels may respond to the signals they receive from their environment, and then use that information to tune their properties and determine the type of information that gets to the lymph node. This, in turn, could influence which types of immune responses get activated or suppressed. That’s really going to be at the core of our work moving forward.

We know that the transport of information is both through the movement of cells and of fluid, which can initiate new signaling in the lymph node and also relieve the tissue itself of certain types of signals. As all of these things get transported in an active manner to lymph nodes, they’re going to determine the types of responses that occur.

And that’s really fundamental to our hypothesis, which is ultimately interested in understanding all of the ways in which these lymphatic capillaries integrate the information of their surroundings. An infection is different from a tumor, which is presumably different from a wound. So, how do these subtle differences in tissue environments tune the lymphatic vessel function to regulate the body’s immune response.

Arthur N. Brodsky, PhD:

I want to move on to the future work you have planned. We’ve been talking about lymphatic vessels in the context of how they work naturally and how they can influence natural immune responses. Now, you want to take this a step further by exploring how these vessels could be manipulated to enhance immunotherapy’s effectiveness. How do you plan to pursue this approach?

Amanda W. Lund, PhD:

That’s exactly where we want to go. If we can understand the natural signals that regulate lymphatic vessel function and the different signals that are present in these different contexts, then perhaps we could develop strategies to specifically activate their function in order to regulate the type of immune response that we initiate in that tissue. So, if there are specific functions that the lymphatic vessels acquire in the context of infection, maybe that’s something we want to mimic in the context of tumors, in order to promote their elimination.

You could even go the other way and think about the situation in the context of autoimmunity, where the immune system accidentally attacks healthy tissue. Here, we would want to see how we could short circuit the immune responses to stop these damaging attacks. Overall, I think the questions that we’re asking are going to lead us to new and interesting ways of thinking about how we use the lymphatic system to drive immune responses against tumors, both in terms of quality and quantity.

Arthur N. Brodsky, PhD:

On one hand, these lymphatic vessels provide a way for T cells—perhaps the most powerful immune cells in our bodies—to become activated and subsequently enter tumors, where they can then attack. But these T cells, as you’ve mentioned, can also essentially be forced to leave tumors through the lymphatic system. Obviously, this wouldn’t be a good thing. We want the T cells to stay in the tumor and keep on eliminating cancer cells. Could you elaborate on this concept and potential strategies to address it?

Amanda W. Lund, PhD:

Initially, we became interested in knowing how these vessels influenced the activity and migration of dendritic cells. These immune cells interact with T cells and help coordinate overall immune responses against threats, including cancer.

As we were studying how dendritic cells exit from tissues into the lymph nodes, we wanted to know what other immune cell subsets were using this pathway in cancer, so we adapted a tool developed by another group and used it to trace cells that were in tumors and moved to the lymph node.

And we found that the vast majority of the cells that were leaving were T cells. This led my lab to want to understand what are types of T cells are leaving, what signals tell them to leave, and are the T cells that are leaving capable of killing tumor cells. And if they are, it’d be perhaps advantageous to keep them in the tumor. There’s a lot of interest right now in the signals that retain T cells as well as work showing that the T cells that are retained in the tumor are receiving these chronic signals that “exhaust” them and render them dysfunctional.

Fortunately, there are ways of targeting that exhaustion. Checkpoint immunotherapies that target the PD-1/PD-L1 pathway are a great example. But the question we’re pursuing is how can we boost that pool of T cells even more? If we understand the signals that are telling the other T cells to leave, can we inhibit those signals in order to boost the numbers of T cells within the tumor? If so, this could make these existing checkpoint immunotherapies even more effective.

So, we’re really excited about this. It’s interesting to think about how recirculation of these T cells might be co-opted by the tumor. In other words, the tumor may set up barriers that prevent the T cells from interacting with their target and instead they get shuttled back out through the lymphatic system.

Moving forward, we have many different experiments set up to interrogate the mechanisms behind this behavior. We also want to ask whether or not these mechanisms could be targeted in order to enhance the effectiveness of existing immunotherapies or potentially new ones.

Arthur N. Brodsky, PhD:

I’m glad you mentioned the checkpoint immunotherapies because that’s where I want to go next. Obviously, one way for a tumor to protect itself would be to make T cells leave the tumor environment so they can’t exert their effects anymore. But, as you mentioned, tumors can also shut T cells down through these immune checkpoints. So even if the T cells remain in the tumor, they aren’t actually doing their job and attacking the tumor.

Checkpoint immunotherapies can block these pathways—especially the PD-1/PD-L1 pathway—and prevent T cells from being shut down. They can even potentially re-invigorate T cells that have become exhausted so they become active against the tumor again. As a whole, these treatments have been relatively successful in the clinic, at least in several cancer types. While we’ve known that tumor cells and other cells in the tumor environment can express these checkpoint molecules, there hasn’t been as much focus on how the lymphatic vessels might also be expressing these checkpoints.

Amanda W. Lund, PhD:

Right. It’s important to understand that these immune-suppressing mechanisms are normal mechanisms that are co-opted by tumors. Normally, healthy tissues use these pathways to help resolve immune activity and prevent an overactive response that causes damage.

In that light, it makes a lot of sense that it‘s not just tumor cells that can activate these checkpoints. All of the other cells that are present in that tissue where the immune response is taking place would also do so as a protective mechanism to preserve tissue structure and function.

That’s one perspective. The other is that if you look in the lymph node, although it’s a critical site for the activation of immune responses, those structures can also suppress immune responses when necessary and that lymphatic vessels are a critical piece of this response.  What we found is that in tumors, lymphatic vessels do express the immune checkpoint PD-L1, and to a really significant level, and this expression was dependent upon a protein made by T cells called interferon gamma.

So it’s a feedback loop whereby T cells come in, make a lot of interferon gamma, and this activates lymphatics and tumors and lots of things in the surroundings to say, “Okay, it’s time to start protecting ourselves from letting this immune response go too far.” Of course, in tumors we don’t want that protection to happen. We want to allow that immune response to go as far as it can go.

We’ve shown now that if we don’t allow lymphatic vessel cells to adapt in that way we can significantly improve tumor control. This is exciting, but it raises many questions. How exactly is PD-L1 on the lymphatic vessel cell affecting T cell function? At what point while T cells move through the tumor environment are they seeing these signals? What are the other lymphatic signals that may also affect T cell function?

Read Dr. Lund's Article on lymphatic vessels and antitumor immunity

Arthur N. Brodsky, PhD:

What are the biggest challenges with respect to trying to decode these complex flows of information?

Amanda W. Lund, PhD:

One of the biggest challenges in asking these kinds of questions, particularly in tumor models, is our ability to trace the soluble factors that are coming from the tumor and moving to the lymph node. Currently, this is done mostly by injection of soluble tracers or dyes that you can follow as they move to the lymph node, but of course this results in higher levels of pressure and changes the biophysical nature of the environment, which may affect the transport that occurs downstream. There are also largely inert molecules that may or may not interact with the lymphatic endothelium in the same way as proteins or exosomes or other molecules derived from the tumor.

So, one of the things we’re really interested in moving forward is developing better methods to track the natural proteins made by tumor cells, so that we can see how that information gets delivered to the lymph node. We could also alter the lymphatic vessel biology and then determine how that impacts what gets delivered and the type of immune response that gets started. Those are significant challenges, but this is a really important part of how we think lymphatic vessels contribute to immune responses. Importantly, this could also help us learn more about the role lymphatic vessels play in metastasis, whereby tumor cells migrate to lymph nodes and potentially other organs via the lymphatic system.

We know that the lymph nodes that tumors drain into are where we should see the induction of immune responses, but these are also sites where we often see early immune suppression that is thought to be necessary for metastatic spread. Metastasis and immunity are all linked and I think if we can understand the signals that drive each of these different processes we can start to ask how manipulating one aspect affects the overall lymph node biology.

Arthur N. Brodsky, PhD:

Hopefully your work will help reveal some of the mechanisms behind these complex processes, which would improve our understanding and ability to develop strategies for patients in the clinic. So, before we wrap up, I want to give you a chance to leave us with your overall vision for your work. I know we’ve discussed a lot of the different parts, but in the grand scheme what do you think you’ll be able to accomplish over the next five years, and how do you hope that your work will impact the cancer treatment landscape?

Amanda W. Lund, PhD:

My ultimate hope is that we can place lymphatic vessels permanently into the immune landscape, and I must say it’s wonderful to have that hope supported by the CRI.

Lymphatic vessels are still considered more peripherally with respect to thinking about how natural immune responses are activated and how responses to immunotherapy are regulated. But I think they’re the critical interface between a developing cancer and the body’s immune response against that cancer. From our basic scientific discovery perspective, placing these vessels firmly into the framework of tumor immunology and immunotherapy is an absolute goal of mine.

Additionally, as we’ve learned more about the fundamental mechanisms through which lymphatic vessels regulate immune responses, we now want to figure out how to leverage that information to tune immune responses and improve a variety of immunotherapy approaches, including strategies like cancer vaccines. We can think about manipulating the tumor environment itself to affect lymphatic function. We can think about how best to time combination therapies to take advantage of the role lymphatics play and how they respond and interact to the tumor and immune system.

Ultimately, I think this work will have a critical impact on the treatment landscape for patients, by using what we learn to design novel strategies to amplify immune responses against cancer in patients. This will be especially important for the patients who don’t currently respond to current immunotherapies. We hope that we can push them into the responding realm. That’s the ultimate translational goal of our work.

Read Dr. Lund's Article on lymphatic vessels and antitumor immunity

Photos courtesy of Dr. Amanda Lund.