Researchers from the Weizmann Institute of Science have identified memory B cells in women with ovarian cancer that are capable of migrating to the tumor and producing targeted antibodies. The finding may advance the development of new vaccines and immunotherapies.
While we tend to quickly forget that we have been sick or that we have received a vaccine, the immune system remembers well. For years, memory B cells – antibody producers that have previously encountered the disease agent and have been trained to recognize and attack it quickly and effectively if it returns – are stored in the lymph nodes. Now, scientists from Prof. Ziv Shulman At the Weizmann Institute of Science, there are memory B cells that are also active against internal enemies – cancer cells. They identified in cancer patients that these cells are capable of migrating to the tumor, taking action, and producing effective antibodies. The new study, whose findings Published today in the scientific journal Immunity, promotes the development of vaccines and immune memory-based therapies against cancer.
The immune system has hundreds of millions of B cell clones in its arsenal, each of which produces a unique antibody to a pathogen—a protein that recognizes a target and neutralizes it or activates other immune cells against it. When the clone encounters the target for the first time, its antibody binds loosely to it and provokes a weak response. So some of the cells enter “germinal centers” in the lymph nodes, undergo genetic changes and strict screening, and emerge with their antibodies more effective. Some of the trained cells immediately become active antibody producers, while others develop into memory cells, which lie dormant in the lymph nodes and are quickly and powerfully activated there in the event of a repeat exposure.
In recent years, it has become clear that B cells penetrate cancerous tumors and produce antibodies to cancer cells. In a 2022 study, Identified Prof. Shulman's group has identified such cells in ovarian cancer. However, it was unclear whether memory cells are also formed that are capable of providing long-term immune protection from cancer. In the new study, led by Dr. Nahum Nathan from Prof. Shulman's lab, the scientists examined the immune cells in samples of tumors and lymph nodes adjacent to them. The samples were collected from 11 patients with the most common type of ovarian cancer (HGSOC), in collaboration with Prof. Ram Eitan and Dr. Oded Raban from Rabin Medical Center. The scientists discovered to their surprise that most of the cells in the lymph nodes adjacent to the tumor were memory B cells.
"We feared that the antibodies would attack human cells indiscriminately, but in fact they turned out to be a targeted weapon against cancer that had spread."
"Since there were no previous reports of effective immune memory against cancer, we doubted the importance of the discovered cells but gave them a chance," describes Prof. Shulman. "We polished their genetic 'recipe' for antibodies, and artificially produced them in the laboratory. We were amazed when more than a third of the antibodies bound strongly to ovarian cancer cells. Since cancer cells are originally healthy cells of the body itself, we were concerned that the antibodies would attack human cells indiscriminately, but in fact they bound less well to other cell types. In other words, the memory cells turned out to be a targeted weapon against ovarian cancer."
The cells discovered are inactive in the lymph nodes – the natural site of the immune response – but that does not mean they have fallen asleep in guard. “We found B cells in the tumor that have just been activated and are from the same lineage as the memory cells in the lymph nodes,” says Dr. Nathan. “The findings indicate that anti-cancer memory B cells are able to migrate from lymph nodes to the tumor, enter training camps there and produce an effective immune response. In doing so, they participate in a long-term immune fight against cancer – a discovery that may advance the development of innovative treatments for ovarian cancer and cancer in general.”
From immunological memory to cancer vaccine
The last decade has seen a paradigm shift in cancer treatment with the development of immunotherapy – a therapeutic approach that harnesses the patient’s immune system to fight cancer. Some of these treatments are inspired by the principles of routine vaccines that we are familiar with, but unlike classic vaccines designed to prevent a disease, these vaccine-based treatments are designed for people who have already had it. Most vaccines that we are familiar with, such as coronavirus or flu vaccines, are based on exposure to a substance that simulates a disease agent in order to stimulate the creation of memory B cells that will effectively recognize and attack it. The understanding that B cells have the ability to produce immune memory against cancer is promoting the development of active vaccines for various types of cancer as well.
But can these treatments prevent cancer from returning after recovery, as often happens? One reason for tumor recurrence is the emergence of new mutations in surviving cancer cells, which allow them to evade the immune system. In this regard, the scientists revealed an encouraging finding – some of the memory cells they discovered produce antibodies to a key protein in the cancer that is important for its ability to spread. It can be assumed that cancer cells will have difficulty coping with a change in essential proteins, and therefore antibodies directed against them may provide long-term protection.
The source of memory problems
Another question that preoccupied the scientists was why the discovered memory cells are not activated in the lymph nodes. To decipher what prevents their activation there, the team, led by Dr. Liat Keren from the institute, identified a population of phagocytic cells (macrophages) that suppress the creation of training camps in the lymph nodes, and thus the activation of B cells. The scientists watched live through a microscope as macrophages specifically engulfed B cells that were in the training stages.
"This phenomenon is not unique to cancer," emphasizes Prof. Shulman. "In inflammatory bowel disease, we found that the more suppressive macrophages there are in the lymph nodes, the fewer training camps are formed, and it is possible that there are dormant immune memory pools for a variety of diseases. In the future, it may be possible to damage the phagocytic cells, thereby activating the full power of immune memory. Alternatively, increasing their activity may make it possible to suppress an immune response that has gotten out of control, for example in autoimmune diseases in which the immune system mistakenly attacks healthy cells."
Also participating in the study were Dr. Philip Paparoditis, Dr. Liat Stoller-Barak and Dr. Roy Mazor from the Department of Systemic Immunology at the Institute; Dr. Avital Serosi Portugese, Dr. Roni Belcher, Revital Ronen and Inbal Nachman from the Nancy and Stephen Grand Israel National Center for Personalized Medicine at the Institute; Dr. Idan Milo from the Department of Molecular Cell Biology at the Institute; Dr. Adva Levy-Barda, Dr. Natalia Yanichkin, from the Rabin Medical Center (Beilinson and Sharon); Dr. Nicholas Burkarding from Washington University in St. Louis, Missouri; Dr. Ina Goliand and Dr. Tomer Meir Selma from the Department of Life Sciences Research Infrastructure at the Institute; Dr. Liat Aligur from the Department of Veterinary Resources at the Institute; Prof. Irit Sagi from the Department of Immunology and Biological Regeneration at the Institute; Goni Hot-Shiloni and Dr. Ilan Kent from Sheba Medical Center Tel Hashomer; Prof. Menachem Gross and Prof. Ariel Tenenbaum from Hadassah Medical Center, Jerusalem.
Short FAQ
What did the researchers discover?
The researchers identified in women with ovarian cancer memory B cells that are capable of migrating from the lymph nodes to the tumor and producing antibodies against cancer cells.
What are memory B cells?
These are immune system cells that are retained after previous exposure to a biological target, and can respond quickly if they encounter it again.
Why is the finding important?
He suggests that the immune system may also have an active memory against cancer cells, and not just against external pathogens such as viruses and bacteria.
Is this a ready-made cancer treatment?
No. This is basic research, but it may help in the future development of therapeutic vaccines and immunotherapies against ovarian cancer and other types of cancer.
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