From Autoimmunity to Cancer Cures: How Diabetes May Hold the Key to Improving Immunotherapy, with Dr. Andrea Schietinger

Biologically, cancer and autoimmunity don’t seem to have much in common. In fact, they appear to be opposites. In cancer, abnormal cells should be eliminated by the immune system’s T cells but often aren’t, whereas in autoimmunity healthy cells that shouldn’t be eliminated by the immune system are. In type 1 diabetes, the immune system attacks normal cells in the pancreas. As with other autoimmune diseases including rheumatoid arthritis, lupus, and other chronic conditions associated with a hypervigilant but misguided immune system, type 1 diabetes reveals how uncomfortable and even dangerous an overactive immune system can be when normal organs are targeted for immune attack.

But what if scientists could figure out how self-reactive T cells involved in autoimmune disorders can continue doing damage to healthy organs when more helpful T cells that target malignant cancer cells can become exhausted or otherwise dysfunctional over time? Could we use this information to create cancer-targeting T cells that are better able to sustain their attack against cancer cells and tumors? That’s exactly what Andrea Schietinger, PhD, a CRI Lloyd J. Old STAR at Memorial Sloan Kettering Cancer Center hopes to learn by looking more deeply into the immune-based causes of type 1 diabetes.

Recently, she made a discovery that surprised even her: the dev­­elopment of type 1 diabetes requires a specialized population of stem-like T cells that constantly replenish the supply of killer T cells that target healthy pancreas cells.

We caught up with Dr. Schietinger, who published this exciting breakthrough in the prestigious journal Nature, to learn more about her next steps and what this work might mean for the field of cancer immunotherapy.

VIDEO TRANSCRIPT

Arthur Brodsky, PhD

Hello, I’m Dr. Arthur Brodsky, assistant director of scientific content at the Cancer Research Institute (CRI), and today I’m grateful to be joined by CRI Lloyd J. Old STAR Dr. Andrea Schietinger of Memorial Sloan Kettering Cancer Center. Welcome, Dr. Schietinger!

Andrea Schietinger, PhD

Hello. Hi Arthur.

Arthur Brodsky, PhD

Your work focuses on one of the central paradigms of cancer immunotherapy, which is that as T cells are waged in this battle against cancer over a long period of time, they can sometimes become exhausted and dysfunctional. First, maybe you could provide an overview of what we understand at the moment about T cell exhaustion in the context of cancer.

Andrea Schietinger, PhD

When a tumor develops, it develops in a certain tissue and the cancer patient has immune cells that are specific for the cancer cell. Over the last year, it became clear that these immune cells can infiltrate into tumors, they can recognize the cancer cells, but they very, very rapidly lose their ability to kill the cancer cells. So, one of the big questions in the field is why? And how can we prevent the immune cells that infiltrate and recognize the cancer cells from losing their effector function? One of the key mechanisms that was identified recently was the fact that the immune cells constantly get stimulated with specific antigens. These are molecular structures on the cancer cells that T cells encounter. And through this chronic antigen stimulation and antigen encounter, the T cells over time become exhausted. They lose their effector function and that allows the tumor to progress. Ultimately, if we don’t do immunotherapeutic interventions, cancer can take over and kill patients.

Arthur Brodsky, PhD

It’s great that we have been able to make this progress of recognizing this T cell exhaustion, and in some patients the checkpoint immunotherapies can work to overcome this exhaustion. But unfortunately, in most cases and in most patients, this doesn’t work because there’s still much we don’t understand about it. Your search for answers took you in an interesting direction, to type 1 diabetes, which is an autoimmune disease where someone’s T cells attack the cells in their pancreas that produce insulin. At first glance, cancer and diabetes don’t really seem to have anything in common, so why did you decide to pursue this avenue?

Andrea Schietinger, PhD

Our research on type 1 diabetes started a few years ago, when we were really thinking hard about ways to reprogram T cells in tumors. Because we knew that one of the drivers that pushes T cells into this exhaustion, this dysfunctional state, is actually this repeated and persistent encounter with tumor antigen, we asked the question: how can you maintain T cell functionality and not allow them to undergo exhaustion when they are in an environment where they continuously see antigen?

For that we tried to look at other areas where T cells can maintain effector function and continue to kill specific target cells and do not become exhausted, despite being chronically exposed to antigen. And that is an autoimmune T cell. An autoimmune T cell is an immune cell in patients that target a specific organ, recognize their specific antigen on normal cells, get repeatedly stimulated with this normal cell, and attack the normal cells. But here the T cell does not get exhausted and continues to attack targeted cells. As tumor immunologists, we thought maybe we need to look at autoimmune T cell as a role model for how we should reprogram T cells for cancer immunotherapy. So, we started looking in the literature and asked the question: how are these autoimmune T cells that never lose effector function and presumably never become exhausted maintaining their ability to attack? We realized that there was not really a lot known in this area.

With help from CRI, we took on this project and explored a clinically relevant mouse model of type 1 diabetes, where we could track over weeks how autoimmune T cells emerge, how they are genetically programmed to behave, and how they infiltrate the pancreas and never lose effector function.

Arthur Brodsky, PhD

That’s fascinating. Obviously, diabetes is a bad thing, but it’s interesting that from the T cell’s perspective, they don’t know what they’re attacking, whether it’s a pancreas cell, a cell infected by a virus, or a cancer cell. So, you learning how T cells can kill a pancreas cell and persist in this attack, and then figuring out how you can use that against cancers is just so cool. Along those lines, what have you learned from these studies? And what are your next steps as far as taking these discoveries and transforming them into therapies for cancer patients?

Andrea Schietinger, PhD

We made a discovery that I never would have expected, that we would discover the mechanism whereby autoimmune T cells mediate effector function and destroy normal tissue. We found that in the pancreatic lymph node—these are very specialized lymphoid organs, which are, so to speak, the headquarters where the immune cells first encounter the antigen that drains from the pancreas. And in these so-called pancreatic lymph nodes, we discovered a very, very specialized T cell. We call them autoimmune stem-like T cells, which sit in the pancreatic lymph node and constantly generate autoimmune T cells that then leave the pancreatic lymph node and travel to the pancreas and kill the pancreas’s islet cells. This very specialized stem-like T cell that self-renews and constantly replenishes these autoimmune T cells has never been described before. What we found is that it actually takes very, very few of these stem cells in order to mediate type 1 diabetes when you transplant them into a new host (mouse).

Our research has been focused on trying to identify what are the key proteins that are expressed that enables this constant generation of autoimmune T cells that then go to the pancreas. We identified a handful of key proteins, so-called transcription factors that program these T cells to be these very unique stem-like T cells. And one of the exciting next questions for me as a tumor immunologist is to ask, if I now take these transcription factors and these very specific proteins and I express them the same way in T cells that are recognizing cancer cells, would I then be able to create these super stem-like T cells to help patients treated with cancer immunotherapy? That is ultimately the goal. And this is where all our efforts right now are focused, to try to engineer these super stem-like T cells in the cancer setting. And then to see whether they similarly can generate constantly cancer-killing T cells that attack the tumor.

Arthur Brodsky, PhD

That’s fascinating. This whole approach strikes me as figuring out how to work smarter instead of harder. It’s not the size of the T cell army, or how many T cells you have, but having a few of those super ones that can replenish.

Andrea Schietinger, PhD

Exactly, and this is really fascinating research to realize how few of those stem cells are really required. We went down to five cells in transplantation studies, and these five cells were able to mediate type 1 diabetes in these new hosts (mice). It’s really fascinating and that’s where the excitement now is for the cancer immunotherapy field.

Arthur Brodsky, PhD

As you mentioned, your ultimate goal is to take these discoveries and what you learn in diabetes and then apply them to cancer. What are the next steps that you’re pursuing in that regard?

Andrea Schietinger, PhD

Our ongoing research is now to take these transcription factors, the specific proteins that are expressed in these autoimmune stem-like T cells, and to engineer T cells that we can use for immunotherapy in cancer settings. We overexpress or delete these specific genes in T cells that are reactive against cancer cells, and we test them currently in vivo in preclinical mouse models and give immune checkpoint blockade and ask the question of whether now, by engineering these specific, very specialized stem-like T cells that are tumor reactive, can we eliminate established solid tumors.

Arthur Brodsky, PhD

That’s great to hear and I hope we’re able to see some exciting results from that before too long. As I mentioned earlier, no one thinks of cancer and diabetes as related and it’s such an out-there concept that is so important because it does relate to the fundamental immune biology. But with respect to this unique approach, did you ever try to get this work funded before? And did you ever think it would get funded?

Andrea Schietinger, PhD

Well, because I believed in the hypothesis and this cool idea, of course, I was hoping it would get funded. We really believed in it. If we would figure out how autoimmune T cells are programmed, it would help us to understand how we need to reprogram T cells for cancer immunotherapy. We applied initially for a few grants, but unfortunately, they got rejected because it was too high risk. It was possible because of the CRI Lloyd J. Old STAR program, which specifically funds high-risk, high-reward projects for tumor immunology. With the support of CRI we were able to conduct this research over the last few years and identify the stem-like T cells, which we now test for immunotherapy for cancer patients.

Arthur Brodsky, PhD

It’s so important. We’ve made a lot of progress in immunotherapy. But in the last decade this progress has been more incremental than revolutionary. There’s been notable advances with CAR T cells and other types of immunotherapy, but when it comes to checkpoint immunotherapy that progress has still been incremental. I think it is going to take research like yours, that’s not on an immediately obvious path, that takes us in a new direction and provides us those transformative discoveries that then we can use to improve survival for cancer patients.

Andrea Schietinger, PhD

Yeah, this is clearly a project where we were thinking outside of the box. I have been a tumor immunologist for twenty years and I would have never thought that my research would lead me in the direction where we are trying to understand autoimmune T cells. But with the research that has been conducted into what drives T cells and exhaustion, we really thought this mystery about why autoimmune T cells do not become exhausted would potentially be a great opportunity for tumor immunology to use these insights for the treatment of cancers.

Arthur Brodsky, PhD

Absolutely. Well, thank you so much Dr. Schietinger for taking the time to speak with us today. It’s been fascinating hearing about your CRI Lloyd J. Old STAR work. This is exactly the kind of high-risk, high-reward research that we want to support to help bring about more cures for patients. So, I thank you very much for your work and for speaking with us today.

Andrea Schietinger, PhD

Thanks Arthur. And I want to thank CRI and all the supporters of this research that we were able to do it and I hope to come back in a few years for some updates on our research. Thank you!