Experts Speak: A Conversation with Professor Susan Kaech

David Woodland: It is a great pleasure to interview Professor Susan Kaech today. Sue is a professor and director of the NOMIS Center for Immunobiology and Microbial Pathogenesis at the Salk Institute for Biological Sciences. She holds the NOMIS Foundation Chair. Her research focuses on the formation of memory T cells, T cell metabolism, and cancer immunotherapy.

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Susan M. Kaech

Sue conducted her undergraduate studies in Cellular and Molecular Biology at the University of Washington and her PhD in Developmental Biology at Stanford University. Her exceptional contributions to the field have been recognized with numerous awards, including the prestigious Presidential Early Career Award for Scientists and Engineers and the Howard Hughes Medical Institute Early Career Scientist. She was also elected to the American Academy of Arts & Sciences (AAAS) in 2023 and the National Academy of Sciences (NAS) in 2024, further solidifying her status as a leading figure in her field.

Sue, I would like to express my heartfelt congratulations on being awarded the 2024 ICIS-Mentorship Award at the Cytokines conference in Seoul this October. Your achievements are truly inspiring. Congratulations.

Susan Kaech: Thank you, Woody. I’d like to start by thanking ICIS for this mentoring award and my mentees for nominating me. That really means a lot to me. It’s probably the most special kind of award one can receive, given that your lab members are the ones who nominate you.

I often get asked about my mentoring style, especially when interviewing postdocs and grad students. I’ve learned more and more about mentoring over the years and now have a deeper understanding of what it means. The bottom line is that you want your lab members to succeed. So, you invest a lot of time in helping them have all they need to develop into independent, exciting, and impactful scientists who will lead the next generation of research.

So, I invest a lot of time in their scientific work, helping them formulate the questions they study and challenging them to think about how those questions will lead to new and original discoveries in the field. One thing I try to do is help them think about the concepts underlying their work and new ways of thinking about the area of immunology that they will focus on. I want them to think about what is NEW about what they are learning? How will it advance the field?

I’ve also learned over the years that what I most love about mentoring is when the relationship between the mentor and your mentee develops into one that’s between colleagues. It becomes very collegial, especially when the mentee teaches me as much as I teach them. I love it when they come to me with new ideas and teach me about a new area of science that I hadn’t thought of before. Or give me a new perspective to consider about their life before they came to my lab. That aspect has been a lot of fun, especially over the past decade. It becomes a nice balance of mutual respect and admiration for the people you’re working with.

Although I mentor individual scientists for short periods, it’s important to remember that I’m working with them at a very formative period of their lives. They’re at graduate school or postdoctoral associates and trying to become independent scientists. So, I try to support them and teach them not to be afraid to take risks so that they can grow as scientists and people and become more confident in themselves.

Another thing I’m known for is that I’m pretty upfront. I like to be transparent and give honest feedback. I’m rigorous and set a very high bar that my mentees sometimes find quite challenging. I try not to set a bar that’s higher than what I would not be able to do myself, but at the same time, I try to be upfront with them, and I don’t sugarcoat things they can work on developing. In addition, I dedicate myself to continuing the relationship once they leave the lab. I want to take the time to be there for them when they want feedback on various issues. I get texts from my past lab members pretty frequently making jokes, asking me questions, or giving me an update on their life. I really cherish that.

Relatedly, one interesting comment in the ICIS nomination letters that I came to learn about is that they called me a “forever mentor.” I thought that was very cute. But I think it shows my loyalty and continued support for their careers and research programs.

David Woodland: Do you mentor students who are not in your laboratory?

Susan Kaech: Yes, I do reach out, especially in the committees I am on and at conferences. For example, if I have a good interaction with somebody at a poster or during a coffee break, I’ll say, “Hey, don’t hesitate to call me if you’re thinking about a scientific question or just have questions.” I also do this when I visit other institutions to give seminars. Sometimes, I just click with another trainee. Maybe they’re contemplating where to go for a postdoc, even though it’s not in your lab. They’ll say, “Hey, I’m choosing between these two labs. Which one would you go to?” Stuff like that. I like people to feel that I’m open to input on a variety of different topics.

David Woodland: And do you have a mentor or mentors?

Susan Kaech: Yes, I have lots of mentors. I’ve always used my mentors in a contextual and condition-dependent manner. If there are things I’m thinking about and need input on, I will go to the people who can give me the best advice. Indeed, I often get advice or input from multiple people, not just one source. My husband is a scientist, and we frequently mentor each other at home. We obviously experience many of the same things and can easily talk about how best to handle certain situations. So, he’s always been my number-one mentor. And what I learned the most from my past advisors, Stuart Kim and Rafi Ahmed is to “pay it forward.” They always went out of their way to support me or give me advice. Even many years after leaving the lab. For example, if I’m looking at a really big decision or challenge, I always contact Rafi Ahmed and say, “Hey Rafi, what about this? Should I do this? Should I do that? What would you do?” and within hours I get his response offering to talk.

David Woodland: Yes, Rafi is a wonderful mentor. Let’s move on to your scientific program, which focuses on the production and role of memory T cells during infection and vaccination. In broad terms, what’s the current status of the memory T cell field?

Susan Kaech: What we’ve seen over the past 20 years, and what was a lot of fun to be a part of, are the advances in our understanding of the genetic pathways that drive T cell differentiation. We’ve identified many of the genetic players, transcription factors, and the epigenetic machinery involved in driving T cells to different differentiation states. In addition, single-cell approaches and the advent of single-cell RNA-seq have revealed a tremendous amount about the complexity of T cell populations. I was fascinated when those approaches started to reveal that there are not thousands of different types of T cells, but perhaps just dozens.

So, we now have a finite number of different types of T cells. Something that I have been thinking about for a while is that there aren’t just types of T cells and lineages of T cells, but T cells can occupy multiple different states, like on a spectrum, where some states are more stable than others. We have always appreciated the inherent plasticity of T cells, so now the challenge is to determine which states are the most stable and which are more plastic. Coupled with the genetic identification of many of the factors that drive T cells towards these different states, we now have a pretty good understanding of the molecular mechanisms underlying T cell differentiation.

At this point, there are still many important questions about the process of differentiation at the molecular level. Although we have identified many of the players, we have yet to learn how they work together to drive T cells toward distinct differentiation states. And when you look at the roles and functions of these different transcription factors, it’s surprising that there’s not more redundancy. You can knock out different transcription factors and find many factors that lead to the same phenotypes. Why does this occur—that so many factors can be involved in driving the same differentiation state of a T cell, but yet they’re not redundant? Why is this lack of redundancy needed? One problem is that we don’t understand how transcription factors operate in concentration-dependent manners. How do changes in the concentration or activity of different transcription factors affect the state of the cell? So, we’re moving as a field to learn more about how these factors, the molecular players, are operating concordantly and cooperatively to give rise to these different T cell states.

Another area that has become front and center is understanding how T cells adapt to the tissues and environments they migrate to. Related to this, one thing we’ve been focusing on is the metabolic environment—how will the different types of metabolites present in different tissues impact the differentiation and functional status of a T cell? How is the metabolic environment different between lymphoid organs and different peripheral tissues? How are the different types of functional T cell responses in distinct tissues metabolically selected for optimal health and protection? Incidentally, it’s not just the T cells that we’re interested in. It’s all of the immune cells that now infiltrate these tissues and reside there long-term.

Another exciting, and perhaps the most innovative, area of research right now is T cell engineering. This field has really advanced, such that we can now program T cells to adopt certain states, take on new functionalities, and carry cargo with them to different sites. The information gathered from all the things I mentioned above, coupled with genetic screening is really paying off. Being able to play around with how the T cells sense the signals in their environment and controlling their functionality is one of the most innovative aspects of the field that we’ll see over the next 10 to 20 years, or even longer, I imagine.

David Woodland: That’s interesting. You know, I’ve always been puzzled by the diversity of T cells because it seems to be an inordinately complicated system. I find it hard to imagine how it works so efficiently in the context of a specific infection. And yet, in most cases, it works flawlessly.

Susan Kaech: Yes, there’s a lot of sloppiness in T cell differentiation programming. It is not like you go from cell type A to cell type B, or cell state A to cell state B. You have a range. And every population has a range of states. What we don’t know is the collective history of a single cell and how much information it receives at different points in its life. With some of the DNA recording approaches that are coming out, we might be able to learn more about that aspect. But that’s always going to be something that’s very hard to understand.

Another important advance in the memory T cell field is our understanding of human immunology. Donna Farber’s work on studying human memory T cells from many different tissues is fascinating. She has provided us with an amazing wealth of resources. And, of course, the SARS-CoV-2 pandemic has taught us a great deal about how an immune response can change over time, the real impact of vaccines, and how disease severity and pathology can be regulated by the immune response.

David Woodland: What are some of the factors that influence T cell differentiation and how chromatin is remodeled during this differentiation?

Susan Kaech: There are so many factors that influence CD8 T cells. As we learn more about how tissues are organized and the different kinds of physical and chemical constraints they impose, we need to understand more about how T cells sense these environmental factors. They’re certainly involving their antigen receptor, which is a major regulator of T cell differentiation based on the presence of antigen. But layered on that are all the other signals that the cells are integrating. One signal that has received a lot of attention is PD-1. And that’s a question that the immune-oncology field is facing right now—are there other regulators as potent and as important as PD-1?

One area that we need to understand better is the location of different T cell populations in the tissues. How does the spatial organization of T cells, and the various cues they are listening to in those niches affect their differentiation states? Indeed, the data indicate that the spatial segregation of T cells is based on their differentiation states to a large degree, a concept that you began teaching us several years ago Woody. So, it’s a feed-forward pathway. However, there will also be different levels of regulation or suppression occurring in these different environments. I believe that the spatial dissection of where cells reside in the tissues or a tumor will be crucial for their differential and functional state. In other words, where are most effector cells? Where are the progenitor cells? Where are the most exhausted and dysfunctional cells? That’s what we will learn with the spatial and transcriptomic imaging technologies that are now becoming more available.

Relatedly, another factor I think about a lot is the metabolic landscape of cancer. Specifically, when you have cells that are in juxtaposition with one another, how do the metabolic changes that occur in one cell, like the tumor cell, influence neighboring cells in terms of their metabolic states? Are they competing for nutrients? Are they sharing nutrients? Are they developing complementary or cooperative types of metabolic arrangements? How will that influence the differentiation and function of the immune cells in the environment? I think that’s where we will learn the most about the fitness of the cells in different environments and how they can be suppressed and/or functional.

David Woodland: What are your laboratory’s most significant findings in this area?

Susan Kaech: One significant finding is that there are a lot of lipids in the tumor microenvironment, more so than in healthy tissues. This is probably due to the high levels of cell death in tumors that produce lots of cellular remnants and debris, or for other reasons that we need to figure out. The increase in the abundance of lipids is sensed by the immune cells through lipid transporters and changes the way in which T cells and macrophages deal with the lipids and this in turn affects how they function and differentiate in this environment.

We’ve also learned that lipids within the tumor microenvironment are more oxidized than normal. This oxidized lipid sends signals to T cells and macrophages to suppress their antitumor functions and convert them into more tumor-promoting cell types.

In one recent lung cancer study that was really fascinating, we found that the alveolar macrophages were being metabolically reprogrammed by the tumor cells. And one of the major changes we saw metabolically was that the macrophages were importing more lipids, burning more lipids, and effluxing more lipids. In other words, they were becoming what we now refer to as “lipid launderers” in the lungs. What was really interesting is we then asked “why they were effluxing more lipids and cholesterol, in particular?” and learned that the macrophage export of lipids was enhancing the oncogenic signaling of the EGFR in the tumor cells. When the macrophage couldn’t undergo these metabolic changes and provide the lipids, the oncogenic EGFR receptor activity within the tumors was less active. So, the activity of the oncogene driving cancer progression depended on the metabolic changes in the macrophage! Pretty crazy, hunh. This is an excellent example of how tumors can metabolically co-opt the local immune cells, to change them into tumor-promoting cells, and possibly metabolically suppress them.

Learning more about these principles and interactions between tumor cells and immune cells will help us understand new pathways of regulation that are important for controlling their function in tumors.

David Woodland: That’s fascinating. Can you share how your groundbreaking work is paving the way for innovative therapeutic approaches in cancer treatment?

Susan Kaech: Regarding the metabolic crosstalk between tumor cells and the immune cells, we need to figure out more of the metabolic changes that drive the immune cells to be more suppressed or tumor-promoting. Then the question becomes— are there ways of blocking that? Maybe those same pathways will be important for fueling the growth of the tumor cells. This would be an excellent target because blocking the activity of that protein or enzyme may slow down tumor growth and also convert the T cells and the macrophages into more antitumor states. I call these potential metabolic vulnerabilities in the tumors as sweet-spots that we need to find more of.

David Woodland: Looking to the future and specifically thinking about your laboratory, what will you focus on in the next two years?

Susan Kaech: We’re still very interested in the metabolic crosstalk between T cells and macrophages. My lab is working a lot on macrophages to understand how they interact with tumors and healthy tissue cells.

One of the questions that most cancer patients ask when they first get diagnosed is, “What can I do to reduce the growth and spread of the tumor?” “Can I do something that will help get rid of the cancer?” And one of the things they typically as about is diet. “What can I eat? Can I eat something that will be better for slowing down or preventing the growth of the tumor?” So, because our work has focused on the role of lipids in promoting tumor progression and suppressing the immune system or turning it into a tumor-promoting state, we have started to ask whether different types of fat can change how tumors grow and how the immune cells function in that environment. I’m really excited about this. Currently, we’re working on a project comparing diets high in omega-6 (the bad fat) versus high in omega-3 (the good fat you get from fish and flax seed). In the case of pancreatic tumors, we’re finding that the tumors grow considerably slower on the fish diet.

We’re now trying to figure out why. What’s happening in the environment that results in slower-growing tumors? This question also gets to the heart of another important question: the role of different types of inflammatory signals and cytokines in promoting tumor initiation and progression versus those that suppress it.

As you go from an inflammatory state, say in the early phases of inflammation, to resolution, repair, and regaining tissue health, lipid class switching occurs. I think that this could be a new way of thinking about approaches to modulate the tumor microenvironment. It’s sometimes said that a tumor is a wound that doesn’t heal. In this sense, maybe we can convert a tumor to a more healing state, where the tumor no longer evades all the normal rules seen in healthy tissues, and goes back to that homeostasis and restraints that keep tumor cells in check. So that’s an interesting larger picture we’d like to explore—diet, lipids, and inflammation in the tumor microenvironment.

Another area that we’re excited about is the discovery that CD8 + T cells can respond to neurotransmitters, specifically adrenergic signals noradrenaline and adrenaline. We’re very interested in moving beyond the sympathetic nervous system to thinking more about how T cells are responding to and maybe influencing neuronal function in peripheral tissues. Clearly, the peripheral immune nervous system interacts with the adaptive and innate immune systems, so we’re starting to explore that.

The last thing we’re excited about is what T cells do in the central nervous system. We’re starting to think more about T cells in the brain. What are they doing? This is a different type of environment, so how do T cells live in this environment? Where do they live? How do they function? We’re also looking at this in the context of glioblastoma to see if we can develop more effective T cell responses against glioblastoma.

David Woodland: As a very successful woman in science, do you have any advice for young women pursuing a research career in science?

Susan Kaech: It has been good to see that our profession is progressing and people now agree and talk about the reality of a glass ceiling for women in science. It’s been more difficult for women to pursue and lead an independent career in research, become tenured faculty, and have more leadership positions thereafter in science. I think everyone has begun to notice this, particularly over the past 10–15 years. What it takes to overcome these inequities is creating opportunity and role models. Men currently in these leadership positions need to ensure that they create to a more diverse set of co-workers and leaders and create successors that will sustain diversity. There are many simple procedural ways to ensure these changes occur. For example, today there are just as many deserving females for awards as there are men…so why not simply ensure there is gender equity in the award disbursement? Seems pretty obvious to me. And this should be true for underrepresented minorities in science as well. As opportunities for women have increased, this has helped create a more inclusive and accepting environment, giving the next generation of scientists in training many new role models. For example, what I have experienced over the last decade is the percentage of female graduate student applications has increased from 50% to 60% and we’re also seeing more women apply to and attain faculty positions. I would like to see universities establish real goals to increase the diversity of their faculty, such that over ten years, 40%–50% of faculty will be women. That would be a great, attainable goal.

One thing I hear often is that women choose not to pursue an academic scientific career because they think it will be too tough for them to do so. They also think it will be too challenging to start a family and so they opt for other career pathways. But what I want to tell people is that academia has incredible flexibility. Yes, it’s a lot of work. You work all the time, but you also have the complete flexibility to work when you want. So it’s easy to go home and do things for your kids, although you’ll probably be working later that night. That level of flexibility is not found in many other professions. I know that many people talk about work-life balance, but I don’t use the word balance anymore. Instead, it’s about integration. It’s integrating your family and hobbies with your science and career.

No one questions today whether or not a woman decides to have a family in science. That might have been true in generations past, but that is not the current status today. And I think it is just a personal decision whether you want to have kids, or not. Still today though, I do hear from women that they have received really inappropriate comments from their colleagues, chairs, or people in leadership and administration. And that always angers me when I hear what ridiculous and demeaning comments they received. I think you need to stand up for yourself if that happens. You need to say something right then and there and make the person who said those things recognize what they said and how they made you feel. And then go talk to your mentors! Let them know what is happening because they can validate your feelings and also step in to rectify the situation if needed. Mediators can be very helpful.

We should never accept inappropriate behavior, no matter what the differences in power are between you and the other person. There is still a need for earnest training to make folks aware of their behaviors and actions, what’s appropriate, and what’s inappropriate to say to women, especially if it’s making them feel inferior. So, we need to ensure that our administration and leaders at universities and research institutes are getting trained better. We also need universities to equalize the leadership positions to better reflect the diversity of our research community. This will all take more time, but I’m optimistic.

David Woodland: Thank you, Sue. And once again, congratulations on your ICIS-Mentorship Award.