Researchers have discovered a new mechanism that allows old cells to avoid immune destruction and accumulate in tissues and thus cause serious diseases * The study offers an innovative anti-PD-L1 antibody treatment that can improve the treatment of chronic and inflammatory diseases such as COPD, cancer, heart disease, and neurodegenerative diseases by improving immune activity and reducing inflammation related to aging
In a new international study led by researchers from the Weizmann Institute of Science, important insights were revealed about how old cells manage to avoid immune destruction and accumulate in tissues during the aging process and chronic inflammation. The study, published in the journal Nature Cell Biology, found that senescent cells that express p16 increase the stability of the PD-L1 protein, allowing them to evade the immune system and contribute to an immunosuppressive environment.
The study was led by Dr. Julia Mayowska and Dr. Valerie Krzyznowski from the Weizmann Institute of Science, in collaboration with researchers from the RWTH University School of Medicine in Aachen, Germany. The study was funded by grants from the Israel Scientific Research Foundation (ISF), the European Research Council (ERC) and the Israeli Ministry of Health.
The laboratory of Prof. Valery Krzychnovsky at the Weizmann Institute of Science has been investigating for years the biological processes that characterize aging and in particular the accumulation of damaged cells that manage to evade the clearing and cleaning systems of the immune system. These damaged cells are apparently responsible for, or contribute to, many of the diseases of aging we know, including degenerative diseases of the brain and nervous system. In the new article in the scientific journal Nature Cell Biology Researchers from the laboratory of Prof. Krizhnovsky present the possibility of fighting the diseases of aging through immunotherapy - the same treatments that revolutionize the field of cancer medicine and stimulate the immune system to act against malignant cells. According to the new research, which was carried out in mice, immunotherapy can be used to stimulate the immune system and make it clear the aging cells and thus possibly curb and even cure a host of old age diseases.
The molecular mechanism
The researchers found that CDK4/6 inhibition caused by p16 prevents the degradation of PD-L1 through the intracellular degradation system, ubiquitin-proteasome, and thus leads to an increase in PD-L1 levels in senescent cells. These cells, among them alveolar macrophages (cells of the immune system found in the lungs and helping to protect the tissue), show an increase in PD-L1 expression which contributes to an immunosuppressive environment and allows them to accumulate in the tissues. "We found that CDK4/6 inhibition by p16 prevents the degradation of PD-L1 through the ubiquitin-proteasome pathway. This is a novel mechanism that explains how senescent cells can avoid immune surveillance and accumulate in tissues during aging and chronic inflammation," says Dr. Julia Mayowska.
therapeutic effects
The study found that treatment with activating antibodies against PD-L1, which recruit Fc receptors on effector cells, leads to the elimination of old cells positive for p16 and PD-L1. This treatment, tested in aging mice and mice with chronic inflammation in the lungs, was able to reduce the number of old cells and reduce the inflammation associated with aging. "The use of activating antibodies against PD-L1 was able to significantly reduce the number of old cells in aging mice and mice with chronic lung inflammation. These results indicate an important therapeutic potential in diseases related to aging and chronic inflammation," explains Dr. Avi Maimon.
The effect of age and inflammation
The study used mass cytometry to investigate the accumulation of senescent cells in the lungs of aging, chronically inflamed mice. p16-positive cells were found to increase PD-L1 levels and thus avoid immune destruction and accumulate in tissues during aging and chronic inflammation. In mice with chronic inflammation, lung epithelial cells showed an increase in PD-L1 expression as a function of p16 expression, while this phenomenon was more pronounced in aged mice. "Our findings show that old cells create an environment that suppresses the immune system and thus allows cells to accumulate and negatively affect the tissue," says Dr. Julia Majowska.
Macrophage cell effects
Alveolar macrophage cells with an old phenotype (cells of the immune system in the lungs that have undergone an aging process, and because of these properties they contribute to chronic inflammation and the accumulation of old cells in the lung tissues), show a high expression of PD-L1 and contribute to an immunosuppressive environment in the lungs. In response to chronic damage, lung epithelial cells express genes that promote an inflammatory response and increase macrophage activation. "The increased expression of PD-L1 in old cells makes it difficult for the immune system to recognize and destroy them. Treatment with activating antibodies against PD-L1 offers a new and effective approach to improve immune surveillance of senescent cells, which can reduce the inflammation associated with aging," explains Dr. Krzyznowski.
In summary, the study revealed that p16 improves PD-L1 stability in senescent cells, allowing them to evade the immune system and accumulate in tissues. Treatment with activating antibodies against PD-L1 increases the immune response and leads to the elimination of old cells. "Our findings present a new insight into how old cells manage to survive and have a negative effect on the body, which can lead to the development of new treatments to improve the quality of life during aging," says Dr. Avi Maimon. "The potential of anti-PD-L1 antibodies to treat aging-related diseases is fascinating and could change our approach to treating aging and chronic inflammation," adds Dr. Lior Roitman. Both are partners in the study.
for the scientific article
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