Senescent Cells Evade the Immune System Like Cancer Cells

The biological processes that underpin aging have long fascinated scientists, offering a rich field of research that could have transformative implications for human health. One of the key players in the aging process is a group of cells known as senescent cells. These are cells that have ceased to divide, a state that is typically thought to be a natural part of the aging process. Unlike normal cells, which die off after completing their division cycle, senescent cells remain alive but are no longer functional in the way that healthy cells are. Instead of dying, they build up in tissues, contributing to a range of age-related diseases, chronic conditions, and inflammation.

In recent years, scientists have turned their attention to these senescent cells, hoping to develop therapies that could delay the onset of aging or treat the diseases associated with it. While the potential benefits of eliminating or neutralizing these cells are clear, it has proven difficult to find a way to efficiently target them with drugs. However, a groundbreaking study published in Nature Cell Biology has revealed a promising approach to tackling this issue, one that could pave the way for innovative treatments for age-related diseases and chronic conditions.

The research, led by Prof. Valery Krizhanovsky’s team at the Weizmann Institute of Science, uncovers a fascinating mechanism by which senescent cells evade removal by the immune system. The team’s findings suggest that these cells, much like cancer cells, employ immune-suppressing strategies that help them persist in the body. Specifically, senescent cells express high levels of a protein called PD-L1, which plays a key role in enabling both cancer and senescent cells to avoid detection and destruction by the immune system.

This discovery was the culmination of years of research into the biological mechanisms of aging, and it builds upon previous work that had identified senescent cells as major contributors to chronic inflammation and a variety of diseases, including lung disorders and heart disease. Krizhanovsky’s team had already shown that these cells accumulate in tissues and organs as we age, impairing normal biological functions and promoting disease processes. The new study reveals that the problem is compounded by the fact that senescent cells, by expressing PD-L1, effectively “clog” the immune system, making it less effective at clearing these unwanted cells from the body.

The study, which was conducted in mice, involved a careful examination of the cellular mechanisms that allow senescent cells to persist. The researchers discovered that senescent cells in the lungs of aging mice had abnormally high levels of PD-L1, a protein that has been well studied in the context of cancer. In cancer, tumor cells express PD-L1 to suppress immune responses, allowing the tumor to grow and spread without being destroyed by the immune system. Similarly, senescent cells take advantage of this immune-suppressing protein to avoid detection, which results in their accumulation in tissues and contributes to age-related diseases.

One of the key questions that arose from this finding was how senescent cells came to overexpress PD-L1 in the first place. The researchers noted that the process of cellular aging involves the simultaneous activation of two opposing forces. On the one hand, aging cells press on the “gas pedal,” remaining highly active and continuing to perform some functions. On the other hand, they also press the “brakes,” which stop the cell from dividing and initiating the programmed cell death process that typically occurs at the end of a cell’s life cycle. This simultaneous action, which can be thought of as a biological paradox, is mediated by proteins such as p16. P16 is a protein that suppresses DNA replication, effectively halting the cell’s normal division process.

Krizhanovsky’s team discovered that the expression of p16 in senescent cells leads to the accumulation of PD-L1. Specifically, p16 interferes with a natural cellular process that would normally mark PD-L1 for degradation, thus allowing it to build up. In their experiments, the researchers found that higher levels of p16 in aging cells were correlated with an increase in PD-L1 expression, which ultimately enabled these cells to escape immune surveillance.

This finding has significant implications for the development of therapies aimed at removing senescent cells. In particular, it suggests that targeting PD-L1 might be an effective strategy for eliminating these problematic cells. While PD-L1 inhibitors have already shown promise in cancer immunotherapy, this study suggests that the same approach could be applied to aging and chronic diseases as well.

The researchers decided to test the hypothesis that targeting PD-L1 in senescent cells could activate the immune system to clear them from the body. They used an antibody that had already been approved for use in cancer immunotherapy, which targets PD-L1 and stimulates an immune response. The antibody was tested in aging mice as well as in mice with lung damage due to chronic inflammation. As expected, the antibody was able to activate the immune system, prompting T cells and other immune cells to attack and remove the senescent cells. This treatment not only reduced the number of senescent cells in the mice but also led to a decrease in the inflammatory proteins that are typically released by these cells.

While the researchers acknowledge that their treatment did not reverse the aging process itself, the results were encouraging. By targeting senescent cells, they were able to reduce chronic inflammation and lessen the burden of age-related diseases, such as lung conditions. The findings also open up the possibility of using immunotherapy to treat other chronic conditions linked to senescent cell accumulation, such as osteoarthritis, cardiovascular disease, and neurodegenerative disorders like Alzheimer’s.

Moreover, the study offers a roadmap for future research into how best to target senescent cells without causing harm to other cells in the body. Because PD-L1 is not exclusively expressed in senescent cells—cancer cells also use it to evade the immune system—the researchers believe that the key to effective treatment will be developing antibodies that can simultaneously target PD-L1 and specific markers of aging. This approach could provide a more precise and effective way to eliminate senescent cells while avoiding unintended side effects.

The results of this study represent an important step forward in our understanding of aging and the role of senescent cells in age-related diseases. It also highlights the potential of immunotherapy to address some of the most pressing health challenges of our time. While much work remains to be done to refine these therapies and bring them to clinical practice, the discovery that senescent cells use the same immune-suppressing strategies as cancer cells is a promising development that could one day lead to groundbreaking treatments for aging and chronic diseases.

Reference: Julia Majewska et al, p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells, Nature Cell Biology (2024). DOI: 10.1038/s41556-024-01465-0