Researchers develop integrated technology to see cells in greater detail

Reviewed by Emily Henderson, B.Sc.August 12, 2020

Invasion of cells into their private spaces-invasion of cell internal functions, decision-making, and communication-can be powerful tools that help researchers develop new immunotherapeutic treatments for cancer. As reported today cell, A research group at the Weizmann Institute of Science, has developed a technology that allows you to observe tens of thousands of individual cells at once in greater detail than ever before. The group, led by Professor Idmitt of the Institute’s Department of Immunology, applied this method to define immune cells that invade tumors and identified a new subset of innate immune cells that “cooperate” with cancer. Blocking these suppressive immune cells in mice significantly enhances the antitumor immune response and kills the cancer.

Amit and his group previously made a considerable invasion of looking at cells when they developed single-cell RNA sequencing-a means of sequencing all the RNA of thousands of individual cells at once. A new method called INs-seq (intracellular staining and sequencing)-research students Yonatan Katzenelenbogen, Fadi Sheban, Adam Yalin, Dr. Developed by Amit’s lab in a project led by Assaf Weiner-enables scientists to measure in addition to RNA, numerous proteins, processes and biochemical pathways that occur within each cell. To do this, they had to develop a new way of getting inside the cell membrane without compromising its genetic content. This abundant “inside information” allows different cell subtypes and activities to be much more finely differentiated than is possible with existing methods, most of which can measure only surface proteins.

In fact, Amit compares these existing cell characterization methods to purchasing watermelon. From the outside, they all look the same, even if they have a completely different taste when opened. Differentiating between seemingly similar cell subtypes, such as suppressor cells and effector immune cells, is very important in the fight against cancer.

The major groups of immune cells have been identified decades ago, but there are hundreds of subtypes with many different unclassified functions.

For example, certain immune subtypes promote cancer, evade the immune system, overreact to viruses, cause tissue destruction, and misbehave in autoimmune syndromes, causing us to It plays the role of attacking one’s own body. Until now, there has not been a sufficiently sensitive means of distinguishing these from other subtypes that look identical to the outside world. “

Fadi Sheban, Weizmann Institute of Science, Research Student

To classify these various immune functions within tumors, Wiseman scientists have used their technology to address the problems researchers have been trying to solve for decades: Why the Immune System The inability to recognize and kill cancer cells, and why immunotherapy often fails most tumor types? In search of an answer, they asked if the cancer would take over and manipulate certain immune cells to “protect” them from the rest of the immune system. “The suspicion that some immune cells are actively “cooperating” with cancer is not as strange as it looks,” Yalin explains. “The immune system often has short-lived meanings, so the immune system has its own mechanism for shutting them down. Cancer uses such mechanisms to drive the production of “shutdown” immune cells. It can boost and prevent immune cells, such as T lymphocytes, that normally kill them from taking action. “

In fact, the team succeeded in identifying T cell-blocking immune cells that belong to a general group called bone marrow cells. Bone marrow cells are an extensive group of innate immune cells derived primarily from bone marrow. This particular subset of suppressive myeloid cells was new, but was distinguished by a prominent signaling receptor called TREM2 previously seen by Amit and his group. This receptor is important for cell activity that inhibits tumor killing T cellsNormally, cells with this receptor are important for preventing excessive tissue damage and dampening the inflammatory immune response following injury. However, Amit also encountered a version of this receptor on other immune cells involved in Alzheimer’s disease, metabolic syndrome, and other immune-related pathologies.

The group’s next step is to develop immunotherapy treatments that use specific antibodies that target this receptor and prevent these immunosuppressive cells from supporting tumors. “This receptor is only expressed in the presence of certain pathologies, so targeting it will not damage healthy cells in the body.”

Preliminary evidence for TREM2 therapy was shown by scientists in a mouse model of cancer with a genetically excised TREM2 receptor. In those mice, the tumor-killing T cells “lived up” and attacked the cancer cells. And the tumor shrank significantly. If treatments based on this finding prove to be effective for human use in the future, they may be given on their own or in combination with other forms of immunotherapy.

Yeda Research and Development, the technology transfer department of the Wiseman Institute for Science, is currently developing this immunotherapeutic antibody for clinical use in collaboration with Amit, and there is already great interest in INs-seq technology. “Unraveling the mechanisms of autoimmune and neurodegenerative diseases and answering the question why the immune system fails to fight cancer, or why most patients do not respond to existing immunotherapy-all of these are immune INs-seq, which may result in specific effects on a subset of, may help researchers identify these specific cells and develop new therapies to treat them. I am thinking,” says Katzenelenbogen.