Immune to Cancer: The CRI Blog




Meet Dr. Andrea Schietinger, One of Our New Lloyd J. Old STAR Scientists

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™.

Dr. Andrea SchietingerOne of these promising STARs is Andrea Schietinger, PhD, of Memorial Sloan Kettering Cancer Center in New York City, who has helped advance our understanding of how the immune system—and T cells, in particular—interact with cancers and how the power of these T cells might be harnessed more effectively against cancer.

Currently, Dr. Schietinger is an assistant professor of immunology and microbial pathogenesis as well as an assistant member in the immunology program at Memorial Sloan Kettering Cancer Center. Previously, she earned a Pharm.D. from the University of Hamburg and a PhD jointly from the University of Chicago and the Ludwig‐Maximilian‐University of Munich. Schietinger, who was a CRI-funded postdoctoral fellow (2011-2012) at the University of Washington in the lab of Philip D. Greenberg, MD, has also been recognized with numerous awards, including the NIH Director’s Innovator Award (2017) and the V Foundation for Cancer Research Award (2015).

Recently, we spoke with Dr. Schietinger 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:

T cells are perhaps the most powerful immune cells in our body and have been a major focus of cancer immunotherapy, especially over the past decade. But these T cells aren’t all the same. For one, there are different types of T cells, such as killer or helper or regulatory T cells, that can vary drastically in their activities. But even within a single classification—killer T cells, for example—there are subsets of cells that are at different stages of development and have different capabilities.

What do we know at the moment about these various T cell states?

Andrea Schietinger, PhD:

Taking killer T cells as an example, first there are newly-formed, naïve T cells. In the context of an infection, once naïve killer T cells encounter a bacterium or a virus and recognize their specific target, they are stimulated to proliferate and become what are known as effector killer T cells. These are highly functional cells that can kill infected or diseased cells and are in some ways considered the “best” T cells from the standpoint of clearing threats from the body.

Ideally, these effector T cells eliminate the infected cells and clear the infection, and then some of these effector T cells go on to become memory T cells that persist and survive in your body for a long time—sometimes up many decades.

These memory T cells just wait in case the threat returns, and if it does, they have an incredible ability to respond quickly by proliferating and making all the killing molecules that are important for eliminating the threat.

Arthur N. Brodsky, PhD:

So, in the context of cancer, obviously, we want to promote immune responses against tumors, but the tumors want to shut these responses down. They try to protect themselves and one way they do so is by “shutting down” T cells via molecules and pathways called checkpoints. To counter this, we’ve developed checkpoint inhibitors that block these pathways and have been probably the most successful immunotherapy approach developed so far.

What do we know currently when it comes to these checkpoints and shutdown with respect to these different T cell states?

Andrea Schietinger, PhD:

When a naïve T cell goes into a tumor, it does not get activated the same way as it would during an infection. The tumor knows how to evade the immune system and avoid detection and elimination, so you end up with a T cell sitting in this growing tumor and becomes non-responsive to the cancer cell.

This is basically a dysfunctional T cell state where it expresses inhibitory receptors called checkpoints. These include PD-1, CTLA-4, and many other pathways that are being explored as therapeutic targets. With immunotherapies that block these PD-1 and CTLA-4 checkpoint pathways, we aim to disrupt this bad tumor-induced signaling in order to convert dysfunctional T cells into highly functional effector-like T cells that can proliferate and then eliminate the tumor as they would an infection.

Arthur N. Brodsky, PhD:

Now I want to turn to the future, and how you’ll be working to answer some of these important questions with the support of the CRI Lloyd J. Old STAR grant. As you mentioned, we can target these checkpoint receptors, like PD-1, that are expressed on the surfaces of T cells. But sometimes that's not enough to keep them in cancer-fighting shape.

So, what are some other factors that can regulate the states and activity of T cells?

Andrea Schietinger, PhD:

Checkpoint immunotherapy has been a great clinical breakthrough that works quite well for some tumor types and for some patients. But many patients and tumor types still do not respond. Now, the big question is why does checkpoint immunotherapy work in some cases but not in others? What distinguishes responders versus non-responders?

Those questions led us to ask if all of the T cells within tumors are the same. Are they all similarly dysfunctional or are there differences? If they are different, what defined those differences?

With respect to PD-1 expression, we found that pretty much all dysfunctional T cells express PD-1. Then, in mouse models, found that not every single T cell with a high level of PD-1 responds to checkpoint blockade the same way. Some you can reprogram and rescue their function, but some were not reprogrammable and we could never push them back into a functional effector state.

These T cells look the same, they have the same levels of PD-1, so why are only some responding to immunotherapy? And the answer to that had to do with epigenetics, which basically involves how the T cells’ DNA is wrapped or packaged. This, in turn, affects how easily certain genes can be turned on or off in these cells.

We found that some T cells have a certain epigenetic state that correlates with the ability to regain effector function. So, when immunotherapy is given, the T cells in this “plastic” state can revert back into functional T cells. But there are other T cells that express PD-1 but do not have this plasticity—their epigenetic state prevents them from regaining effector function. These T cells are fixed, non-reprogrammable.

Without intervention, both these T cell subsets will be dysfunctional within the tumor. But with the use of checkpoint immunotherapy we can revert the first subset back into effector T cells that can successfully attack tumors.

Recently, we found new proteins on a T cell’s surface that can shed light on the epigenetic state of T cells and help us distinguish between these different states. Now, we can go into patients and see if their T cells are in a more plastic or fixed cell state.

And if we see that a patient has a lot of T cells in the more plastic cell state, then it tells us that immunotherapy may help them, by pushing their T cells back into an active state. But if a patient has more fixed T cells, then we need to give additional treatments, for example epigenetic drugs. That is exactly the focus of the research we are now doing with the help of the Cancer Research Institute.

Arthur N. Brodsky, PhD:

You did an excellent job of explaining how uncovering the answers to important basic science questions might be used to develop strategies that can actually help patients in the clinic.

To aid this process, you’ve developed a new mouse model that will allow you to image the cells within tumors, including T cells, cancer cells, and other types of cells that are found in the tumor microenvironment. How will this new tool help you advance your research?

Andrea Schietinger, PhD:

Previously, we examined tumor samples that had been taken during biopsies and were no longer in their natural environment in the body, so we couldn’t see their activity in real time. Now, with this new system, we can zoom into the tumor and follow the cell populations over time throughout tumor development. Or we can give a therapy and then monitor the tumor and immune responses over time to better understand the various interactions, both in cases where therapy elicits a positive response and in cases where the tumor is resistant to treatment.

Seeing is believing. If you can’t see what's happening in the tumor in real time, it will be very hard to arrive at interpretations and conclusions that reflect the real life situation in patients. That’s why I am incredibly thankful that CRI is supporting us because now we have the ability to start doing some of these things and going after some of the questions we couldn’t answer before.

With this mouse model, now we can see how T cells interact with the tumor microenvironment. If we have all of the ingredients that we think should give us a response, but don’t see a response, then we can account for other factors—other molecules, other cell types—and then determine the role they might play in allowing us to turn a non-responder into a responder. This model’s ability to visualize cellular interactions, in real life and in high resolution, will be important for interpreting and pushing the research in the right direction and help us develop approaches to overcome immunotherapy resistance.

Arthur N. Brodsky, PhD:

It sounds to me like when you took out tumors to analyze them before, you were only really getting a snapshot. You could only see what they were like at one point in time, whereas now you're going to essentially have a movie of the situation so you can see how the cells change over time, which will give you more direct insight into their activity.

Andrea Schietinger, PhD:

Exactly. Before, we had to take out the tissue to study it, which means you couldn’t continue to study the mouse. But now, every single day we can come back to the same place and ask what happened over the last 24 hours. That gives us such a powerful dataset of information that we can use to make more informed decisions regarding what is needed in order to make immunotherapy more effective for a given patient.

Arthur N. Brodsky, PhD:

As you just mentioned, the most important goal is to create better immunotherapy strategies for humans. While the mouse model can serve as a great guide and provide answers to some important questions, you ultimately want to figure out what works in these mice so that we can improve care for humans, too. To that end, you are also collaborating with physicians to translate your work into the clinic. Could you share a little bit about your plans in that regard?

Andrea Schietinger, PhD:

Of course. So, I always aim to ask questions that aren’t strictly basic science questions, but also really relevant to the problems that patients and doctors experience in the clinic. Here at Memorial Sloan Kettering Cancer Center (MSKCC), I'm incredibly fortunate to work and collaborate with top notch clinicians who see patients with all types of cancers.

The path still starts at the mouse model. And when we get a finding there, we go across the street and ask the clinicians for human samples so that we can see if what’s going on in the mice applies to humans as well.

One really beautiful example of that collaboration happened when we asked, in the mouse model, what factors actually push T cells to express PD-1 and CTLA-4 and other “bad” inhibitory receptors?

We identified a factor, called TOX, in the mouse system and, while it was very interesting, we were more concerned with whether it had any clinical relevance in humans. We obtained different patient samples from four different types of tumors—breast, ovarian, lung, and melanoma—and we found that this one molecule is highly expressed and leads to the same types of T cells in humans as it did in mice.

Now, we share data and talk with the clinicians almost on a daily basis to figure out how we can translate insights from mice to humans. So, we have a completely translational enterprise here because in the end we want to cure cancer in humans, not in mice, right? That's why this is such a terrific infrastructure here because you work with the best of the best in the hospital and that makes this research so exciting because in the end you want to have an impact on the clinical side.

Arthur N. Brodsky, PhD:

I totally agree, and it’s very inspiring to hear about this promising approach you’re using. So, before we wrap up I want to give you a chance to share your overall vision for the work that you'll be doing as a Lloyd J. Old STAR. What do you hope to accomplish and how do you hope that your work will impact the clinical treatment landscape for cancer?

Andrea Schietinger, PhD:

We are at a very, very exciting time right now with cancer immunotherapy. But we are also realizing more and more that we need to ask the next big question. So, what is next?

While PD-1 checkpoint immunotherapy has helped a lot of patients, now we really need to figure out how we make it so that everyone benefits from and responds to immunotherapy. We have a long way ahead of us and it will not be easy, but if we ask the right questions in the right setting with the right models, and we collaborate with the clinicians, we can potentially get to that point.

Over the next five to ten years, we will explore mouse models of hard-to-treat cancers because I feel like if we can succeed there—like Dr. James Allison did in metastatic melanoma—then there is a chance that we might actually have the same effect in the clinic. By asking questions in tumors that are especially resistant to immunotherapy, we can apply hardcore basic science approaches to figure out why it doesn’t work and then plan our next line of attack from there.

For example, the model that we are establishing with the help of CRI is a really high-risk project but also a high-reward project. And that is the mission of this whole program: to tackle the more risky questions that, if answered, provide the possibility to move the field forward a lot. This kind of funding mechanism is terrific because the more classical funding mechanisms would probably not allow me to ask these types of questions as the CRI Lloyd Old STAR program is now allowing me to do. In that light, I am extremely grateful for CRI’s foresight that is enabling me to carry out this important work.

Read interviews with the inaugural Lloyd J. Old STARS

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