Everyone has a distinct “immune setpoint” that determines the way they respond to diseases and treatments. Matthew Spitzer, Associate Professor at UCSF and scientific cofounder of Teiko Bio, explains how understanding each patient’s individual immune setpoint could be the key to maximizing cancer treatment efficacy.
What is an “immune setpoint” and how does it affect our responses to life-threatening diseases like cancer?
Each individual’s immune system is characterized by a unique homeostatic baseline, called the immune setpoint. The immune setpoint defines how our immune system behaves naturally, in the absence of a disturbance. This is based on our underlying genetics, historical exposures to different infectious diseases, and other types of events that may have impacted the state of our immune system. In the case of cancer, the immune setpoint determines how someone’s immune system will respond to the cancer cells and whether they can control the tumor.
Page Anchor: #characterizing-immune-setpoint – Not Visible On Front“…the immune setpoint determines how someone’s immune system will respond to the cancer cells and whether they can control the tumor.”
How do we characterize an individual’s immune setpoint?
The most common approach is to measure the types of immune cells that are present in someone’s body and look at how those cells are behaving. Cytometry-based approaches have historically been the most common way to do that. We use mass cytometry to measure the expression of roughly 45 different proteins across hundreds of thousands of cells at the single-cell level. Some of those proteins help us identify different types of immune cells, while others give us insight into how those cells are behaving or functioning. It’s been a really powerful tool over the last decade to understand more about the human immune system and how it responds to different perturbations.
We also have technologies that similarly can measure gene expression at the single-cell level. Other types of analyses provide us with complementary information on the chromatin landscape of immune cells, the abundance of circulating proteins such as cytokines and chemokines, as well as T cell and B cell receptors expressed by someone’s adaptive immune cells. These are layers of information that we now have access to, which can give us additional insight into the state of someone’s immune system.
Page Anchor: #immune-setpoint-approach-today – Not Visible On FrontAre these technologies used by doctors today?
Not typically. There are other tools that doctors use to help decide whether a patient is likely to benefit from a drug. However, these approaches still leave a significant amount of uncertainty. For example, doctors currently look for specific mutations that correspond to the signaling pathways that therapies can target. The challenge is that cancers often find ways to escape by evolving and developing resistance. So, while a patient’s cancer might initially benefit from these drugs targeting a specific mutation, the effect may not be long-lasting.
In contrast to these targeted therapies, immunotherapies have the potential to activate immune cells that recognize cancer cells as foreign, and this can result in the formation of long-lived memory cells that protect against cancer recurrence for long periods of time. We have some clues as to which patients are more likely to benefit from immunotherapy, but often these responding patients are difficult to predict using the tools currently available to oncologists.
Page Anchor: #immune-setpoint-better-approach – Not Visible On Front“…immunotherapies have the potential to activate immune cells that recognize cancer cells as foreign, and this can result in the formation of long-lived memory cells that protect against cancer recurrence for long periods of time.”
If that’s the case, what could be a better approach?
Most drugs are initially developed because the pathways that they target were thought to be important in cancer cells or in other types of cells within the local tumor microenvironment. As we learn more about what those drugs are doing in people and in mouse models, it has become apparent that many of them are acting outside of the tumor as well. So, we should really be thinking about interactions outside of the tumor that could be used to activate cells that have the potential to drive new immune responses. Understanding how immune responses outside the tumor associate with clinical response is a real opportunity to better identify those patients likely to benefit.
For example, one of the main types of immunotherapy to treat patients with solid tumors is called a checkpoint inhibitor. Many of these inhibitors block a protein called PD-1 or its ligand, PD-L1. Originally, it was thought that, how many T cells express PD-1, or how many cancer cells or myeloid cells express PD-L1, would be interpretable information that would predict efficacy. This turned out not to be quite as straightforward as we would have thought. For instance, scientists found that many patients who have high levels of PD-L1 don’t necessarily respond well to checkpoint inhibitors. Meanwhile, some patients who don’t have a high expression of PD-L1 respond well.
We’re still working to understand exactly why that is the case. But one of the things we’ve learned is that these checkpoint inhibitors are, at least in part, not only acting on cells that are in the tumor tissue, but also on cells outside of the tumor tissue, including cells in the lymph nodes. These peripheral cells can be activated outside of the tumor, circulate through the blood, infiltrate into the tumor, and kill cancer cells.
“…these checkpoint inhibitors are, at least in part, not only acting on cells that are in the tumor tissue, but also on cells outside of the tumor tissue, including cells in the lymph nodes.”
This suggests that looking only into the tumor tissue is limited because it doesn’t provide you with full insight into one’s immune responses. There is a real opportunity for immune monitoring or measuring the immune setpoint outside of the tumor to understand somebody’s baseline immune state.
Page Anchor: #immune-setpoint-future – Not Visible On FrontDo you think immune profiling will change the way we treat cancer patients in the future?
The immune system provides us a unique opportunity to fight cancer because of its ability to adapt, to keep up with changes that take place in cancer. It clearly has the potential to be very powerful if we can figure out how to effectively harness it across all patients.
I think there are opportunities that we might be missing when we don’t think about important pathways or interactions outside of the tumor. We need to be thinking critically about the variability that exists across patients in their immune states and to what extent they’re likely to be able to mount an immune response to different types of drugs. I think it is clear that there will be great utility for these immune profiling technologies in tailoring treatment strategies for particular patients and in different disease contexts.
The field has made tremendous progress in this area over the last 20 years, and many patients are now experiencing the long-term, durable benefit of immunotherapies. There is a very real opportunity for us as a scientific and medical community to continue making advancements in this area to improve patient outcomes with the latest technologies available.
