A glimpse into the inner world of cells, a close examination of their activity and close monitoring of their internal communication: A new technology developed by scientists at the Weizmann Institute of Science allows researchers to see in greater detail than ever what is happening within tens of thousands of individual cells – at once.
As published today in the scientific journal Cell, using this technology, the scientists discovered a new subgroup of cells belonging to the innate immune system, and “cooperate” with cancerous tumors by suppressing the body’s immune activity against cancer.
Neutralization of these cells in mice has led to a significant improvement in the immune system response against tumors and the eradication of cancer.
The research group led by Prof. Ido Amit from the Department of Immunology has previously made significant progress in the ability to look closely and characterize high-resolution cells, when it developed a method for sequencing the genetic material RNA from each cell separately (single-cell RNA-seq).
The new technology, known as INs-seq (intracellular staining and flooring), allows the activity of intracellular proteins to be measured in parallel with the RNA content, thus characterizing biochemical processes and pathways that distinguish each cell and cell in the various body tissues.
To achieve these results, researchers Jonathan Katzenelnbogen, Paddy Shiban, Adam Yellin and Dr. Assaf Wiener have developed new methods to penetrate the cell envelope without harming its genetic content. The richness of “internal information” revealed to them greatly improves the ability to notice subtle differences in their function and activity Of different subtypes of cells – in contrast to existing methods that allow cells to be characterized only by measuring their envelope proteins, which limits the ability to separate cells with different and sometimes even opposite activities.
Prof. Amit compares the existing methods for characterizing cells with the choice of watermelons: on the outside, all the watermelons are similar, but when you open them, significant differences in taste and texture are revealed. Similarly, the new method makes it possible to distinguish between different subtypes of cells that look exactly the same when viewed from the outside.
Thus, although the major groups of immune system cells have been identified many decades ago, there are many dozens of subgroups that have not yet been identified, and their activity may be significant. “Certain subtypes of immune cells, for example, may help cancer escape the immune system, cause tissue destruction due to an overreaction to the virus, or attack the body tissues themselves, as happens with autoimmune diseases. So far, we have not had a sensitive enough method to distinguish Between these sub-types and others, “explains Shiban.
Using the technology they developed, the scientists tried to examine why the immune system fails to detect and kill cancer cells – and whether cancerous tumors can “snatch” and “manipulate” certain cells of the immune system so that they will be protected from other cells. “Immune responses are usually short-term, so the immune system has mechanisms to stop them, for example through repressive immune cells,” Yellin explains. “A cancerous tumor can take advantage of these mechanisms to recruit repressive cells into the tumor environment – thus preventing other cells of the immune system from detecting and eradicating cancer cells.”
The researchers were able to identify special cells of the innate immune system, which belong to the group of myeloid cells, which suppress the activity of “gut” immune cells called T cells.
This subtype of suppressing myeloid cells has not been known to the scientific community to date. It was detected using the new technology and was characterized by the presence of a receptor called TREM2 on the cell envelope. Most often, cells carrying this receptor are essential for preventing excess tissue damage following injury or calming an inflammatory response, but Prof. Amit and his team have previously identified another role of this receptor on immune system cells involved in Alzheimer’s, metabolic syndromes and other pathologically related pathologies.
Following the findings, researchers are currently developing immunotherapy based on antibodies specific for this receptor. “Because the receptor is only expressed in disease states,” says Dr. Wiener, “damage to it is not expected to damage healthy body cells.” Preliminary findings for the possibility of TREM2-based receptor therapies were presented by scientists in a cancer model in mice. These were silenced, the ability of T cells to attack the cancer improved – and the tumors contracted significantly.
Yeda, the institute’s intellectual property arm of the institute, is currently working with Prof. Amit’s laboratory for the development of an antibody for 2 TREM for clinical use.
In addition, there has been a lot of interest in the new INs-seq technology. “In addition to cancer, identifying new subtypes of immune system cells will allow a deeper understanding of the mechanisms that cause autoimmune diseases, degenerative nerve diseases and many other diseases. INs-seq technology may help researchers identify these subtypes and lead to the development of new therapies,” he said. Says Katzenelnbogen.
Dr. Ido Yaffe, Dr. Demetri Sveticini, Dr. Diego Haytin, Dr. Hamutal Bornstein Owitz, Dr. Adi Moshe, Dr. Hadas Keren-Shaul, Dr. Meirav Cohen also participated in the study. Dr. Xuyang-Yin Wang, Dr. Baugu Li, Eyal David and Dr. Tomer Meir Selma.