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T Cell Receptor Sequences Are the Dominant Factor Contributing to the Phenotype of CD8+ T Cells with Specificities Against Immunogenic Viral Antigens

By November 24, 2023December 6th, 2023No Comments

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This week, Science in Seattle profiles Dr. Jim Heath (pictured). Dr. Heath is President and Professor at the Institute for Systems Biology in Seattle. We discuss why he made the switch from physics and chemistry to cancer immunotherapy. We also discuss the impact of his recent publication in Cell Reports and how his work could have broad implications for personalized medicine for treating both infections and cancers.

This interview has been edited for brevity and clarity. 


Can you provide a brief overview of your lab’s current research focus?

We have a couple of major projects going on. We’re basically concerned about how the immune system is altered by disease and how it can be engineered to help fix disease. For some of that, I run a really big part of a national study on long COVID. I also have a lot of programs in the field of immuno-oncology, developing cell-based therapies for treating certain types of solid tumors. 


What is the significance of the findings in this publication?

T cells are roughly half of your adaptive immune system, meaning the parts of your immune system that remember previous infections. Antibodies and B cells are roughly the remaining half. When you have an infection, you activate these parts of your immune system against the infection. For T cells, that means they will see—in the case of a viral infection—fragments of the virus that are presented on the surface of infected cells. This will induce responses from the T cells. In some cases, they will become cytotoxic and kill the infected cells. Other T cells will remember the virus so that if the virus reappears, they can send out signals to recruit other T cells to the infection site. 

There are a lot of subtleties here. A longstanding mystery in immunology, specifically in T cell biology, has been once a T cell sees the fragment of the virus, what determines what it does? What determines whether it becomes a memory T cell, a killer T cell, or any of the other potential possibilities for that cell? 

There have been a lot of different hypotheses in the past—biological environment, internal signaling, etc.—but what we showed is that only one thing matters: the T cell receptor gene. Similar to how antibodies shuffle their DNA at a particular region, called the variable region, to allow for one protein to turn into trillions or quadrillions of proteins, the T cell receptor gene is shuffled to recognize many things. That was the focus of this paper.

So, if you have a viral infection and your cells are producing fragments of the virus on the surface for T cells to see, you may get a hundred different types of T cells reacting with that one viral fragment. That moment is when the T cells can decide whether they become memory or cytotoxic T cells. Our study shows that the only thing that matters is that particular T cell receptor gene. Once you shuffle the genes, that T cell receptor is set. When it divides, you will retain that same receptor.

So why is that important? Imagine you have a patient that is not responding well on their own against a disease or cancer. If you know the ruleset for the T cells that will recognize the disease fragments, then you can engineer an immune response. Effectively, you can go to a library and pick out the right T cell receptors, so that you can have the right immune response against the infection or the cancer.


What kind of impact do you hope your research will have? Is that based on creating these personalized therapeutics?

Yes. Right now, we’re planning a clinical trial for patients who have cervical cancers or head and neck cancers. We’re using engineered T cells to attack those cancers. We chose those two cancers because they are almost always driven by human papillomavirus. At the moment, we’re identifying lots of T cells that recognize fragments of human papillomavirus and working out the rulesets. 

So if we give a patient a T cell therapy, we want to give them T cells that will remember the cancer as well as T cells that will kill the cancer so the cancer doesn’t come back. That’s not done in immunotherapy now, but it’s something that will be enabled by our work. 


What are the next steps for this research? Can you elaborate on the intersection with the long COVID side of your work? 

It’s allowing us to understand, for example, in patients who get long COVID, whether their immune system remembers the COVID infection very well or whether they’ve got viral residues that are left in the body. If those residues or fragments somehow emerge when, for example, the tissue dies, does your immune system have to re-learn them all over again? 

In long COVID, we’re trying to understand the importance of immunological memory in sequela from chronic symptoms. In fact, in this paper, we showed that we could understand this ruleset of T cell receptors and what a T cell does when it sees fragments of the virus. We did this for three different viruses: flu, cytomegalovirus, and COVID.


What do you think are the biggest challenges facing life scientists in your field today?

I’ll give you two answers. First, I think about cancer. The oncology field has made amazing progress in treating what are generally known as liquid tumors, like leukemias, and certain solid cancers, like melanomas and maybe one or two breast cancers. But we really haven’t learned how to harness the immune system to attack most solid tumors. That’s still an outstanding problem. We’re working on at least one approach towards doing that. 

The other scientific opportunity that has really been neglected through the years is understanding the detailed nature of chronic disease, like lupus, multiple sclerosis, rheumatoid arthritis, and chronic fatigue. One of the reasons why we’re studying long COVID is because it has given us insight into some of these other chronic diseases. These have always been the kind of things that you go to the doctor, they do a lot of tests, they hum and haw, and they tell you to go get more rest. They don’t really have any solutions for you. But I think we’re beginning to have the tools that allow us to begin to have some understanding of the nature of chronic disease. As we begin understanding the human immune system and all its machinery in gory detail, we’re going to begin understanding chronic disease.


Why did you get into cancer research specifically?

That’s a great question. My training is not as a biologist. In fact, I’ve never taken a biology course. I was more of a physicist/chemist for much of my academic career.

A few years ago, I was offered a job at Caltech—one of the top jobs in one of the top departments in the world. And I thought, “well I’m actually gonna actually do something different now that I moved.” I thought that the immune system and biology really represented the great challenges of the 21st century, so I immediately began working in cancer immunotherapy before anything was established in that field. That struck me as the most compelling approach towards treating cancer. 

We spent a decade in that area before anything started working. Then we and several other people made major breakthroughs that made cancer immunotherapy a viable treatment. We’ve just been building up since then.


Is that part of the reason why you moved up to ISB from Caltech? 

Yes, because at ISB, we have an alliance with the Providence Healthcare System. That alliance gave us a 50-hospital system with which to begin translating the types of findings we do into clinical benefits. When you’re in biotech, people say that it takes 10, 15, or 20 years between a fundamental discovery and its clinical impact. So my goal in coming to ISB was to try to shorten the window between basic discovery and patient benefit. 


This research is funded by The Parker Institute for Cancer Immunotherapy, The National Cancer Institute, and The Andy Hill Cancer Research Endowment (CARE) Fund.


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