Tumor sample from a human patient with the most common type of lung cancer (adenocarcinoma). Senescent cells are notable for their expression of p16 (red) and PD-L1 (green) proteins. Cell nuclei are in blue (Weizmann Institute)
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Immunotherapy eliminates senescent cells in mice, according to a Weizmann Institute study
- The research published in Nature Cell Biology suggests that immunotherapy could treat age-related chronic diseases.
- Scientists discovered that senescent cells evade the immune system using the protein PD-L1 similar to cancer cells.
- An antibody used in cancer treatments significantly reduced the number of senescent cells in mouse models.
The essential: a study of Weizmann Institute revealed that senescent cells, responsible for chronic degradation and aging, block the immune system using the protein PD-L1. Like cancer cells, senescent cells avoid being eliminated by the body. Researchers demonstrated in mice how an immunotherapy approved for cancer activates the immune system, reducing the number of these cells and inflammation. The finding opens a new way to treat age-related disorders.
Why it matters: Research could revolutionize the treatment of aging and chronic diseases.
- The elimination of senescent cells could delay the onset of diseases associated with old age.
- This approach may be key to reducing chronic inflammation and improving quality of life.
- It opens the possibility of new applications of immunotherapy beyond cancer.
Prof. Valery Krizhanovsky y Dra. Julia Majewska (Instituto Weizmann)
When a sink overflows, the flood is usually due to a blockade that has formed in the drains. Similarly, as we grow oldour body is flooded by aged or senescent cellswhich have stopped dividing, but instead of dying, remain active and accumulate in body tissues.
Recent studies have shown that getting rid of these cells could delay age-related diseases, reduce inflammation and prolong life. However, despite the great potential, currently there is no medicine that can act on these cells directly and efficiently.
Now, researchers from Weizmann Institute of Sciences They propose an alternative approach. In a study published in Nature Cell Biologyreveal that senescent cells They accumulate in the body, obstructing the immune system., thus preventing its own elimination. Scientists demonstrated in mice how to unlock this lock using immunotherapy, the new generation of treatments that is revolutionizing anti-inflammatory therapy cancer. These findings could pave the way for a Innovative treatment of age-related diseases and other chronic disorders.
Professor Valery Krizhanovsky’s laboratory in the Weizmann Department of Molecular Cell Biology has long been studying biological processes characteristics of aging, specifically, the involvement of senescent cells in age-related diseases and chronic inflammation.
A mathematical model developed in 2019 by Professor Weizmann Uri Alon in collaboration with Krizhanovsky, predicted that, while senescent cells are removed from a young body in a matter of days, in an aged body they achieve delay your own elimination. The new study, led by the Dr. Julia Majewska and the Dr. Amit Agrawal, reveals the mechanism that makes this possible: how senescent cells evade the immune system in the same way that cancer cells do.
Lung tissue from a human patient with chronic lung damage. Senescent cells are notable for their expression of p16 (red) and PD-L1 (green) proteins. Cell nuclei are in blue (Weizmann Institute)
The researchers discovered that senescent mouse lung cells express large amounts of proteins that suppress the immune system, in particular la PD-L1. This protein, well known in oncology, is a key target for the development of new anti-cancer drugs, since it has been shown that cancer cells use PD-L1 to reduce the capacity of the immune system to recognize and destroy them.
The question, however, is how this occurs. overexpression of one immunosuppressive protein. The process of cellular aging can be compared to stepping on the accelerator and brake at the same time: stepping on the accelerator means that the cell remains very activewhile, on the other hand, stepping on the brake takes the cell to the end of its normal life cycle and stops their division (precisely why senescent cells are sometimes called “zombis”). A key component of brakes is the p16 proteinwhich suppresses DNA replication in the cell.
In their study, the researchers found that there is a correlation between the increase in p16 during cellular aging and the increase in PD-L1 levels. They also discovered the molecular mechanism responsible for this increase: p16 suppresses a natural cellular process which marks the degradation of PD-L1.
However, senescent cells are not only important in aging. In previous studies, Krizhanovsky’s team had shown that the accumulation of these cells contributes to diseases chronic pulmonary and other disorders. The current study shows how PD-L1 protein levels increase not only during aging, but also in a mouse model of chronic obstructive pulmonary disease, which is more common in smokers. Additionally, researchers discovered that people with this disease have senescent cells that express high levels of p16 and PD-L1.
Dr. Amit Agrawal (Weizmann Institute)
Once it became clear that the senescent cellsjust like the cancerous, They express high levels of PD-L1, which helps them evade the immune system, the researchers hypothesized that this knowledge could be used to target senescent cells with a relatively high degree of precision. They decided to take advantage of a antibody which had already been approved to treat several types of cancer, using it to identify PD-L1 on cell membranes and activate the immune system against it. The researchers tested this antibody in old mice, as well as in mice with chronic inflammatory damage and short-term in the lungs. As expected, the antibody activated T cells, immune system warriors, and other immune cells, leading to a reduction in the number of senescent cells.
“While the treatment we examined did not stop the aging clock, it did manage to get rid of senescent cells in mice and even reduce the release of small proteins that promote inflammation in old age and chronic diseases,” Krizhanovsky says.
“Since PD-L1 is expressed in large quantities not only in senescent cells, we believe that the key to developing a specific and effective treatment will be antibody engineering that can identify two proteins at the same time: PD-L1 and an indicator of aging. “This discovery raises hopes that immunotherapy could be used in the future to treat not only cancer, but also age-related diseases and chronic inflammation.”
Also participating in the study were Dr. Avi Mayo, Lior Roitman, Ilanit Sopher, Dr. Avi Maimon and Prof. Uri Alon from the Weizmann Department of Molecular Cell Biology; Rishita Chatterjee and Dr. Jarmila Kralova of the Weizmann Department of Immunology and Regenerative Biology; Dr. Tomer Landsberger, Yonatan Katzenelenbogen and Prof. Ido Amit from the Weizmann Department of Systems Immunology; Drs. Tomer Meir-Salame and Efrat Hagai from the Weizmann Life Sciences Basic Facilities Department; and Juan-Felipe Pérez-Correa and Prof. Wolfgang Wagner of the Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
Professor Valery Krizhanovsky’s research is supported by the EKARD Institute for Cancer Diagnostic Research; the Sagol Center for Brain Aging Research; the Nella and Leon Benoziyo Center for Neurological Diseases; the Shimon and Golde Picker – Weizmann Annual Scholarship; and the Quinquin Foundation.
Professor Krizhanovsky holds the Georg F. Duckwitz Chair in Cancer Research.
