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The new players in the war on cancer

Our immune system has a powerful and accurate weapon to destroy bacteria and viruses. It is possible that in the future it will also be possible to harness it against malignant tumors

Natural cancer antibodies (green) bind to ovarian cancer cells. Cell nuclei in blue. Photographed using a confocal microscope
Natural cancer antibodies (green) bind to ovarian cancer cells. Cell nuclei in blue. Photographed using a confocal microscope

The new generation of cancer treatments does mobilize the immune system of the patients, but it is far from utilizing the full defensive arsenal of the human body. In fact, immunotherapy treatments against cancer often rely on the same defense mechanism: the ability of the immune system's T cells to fight the tumor. BNew research published in the scientific journal Cell, scientists of the Weizmann Institute of Science indicate a new therapeutic direction: immunotherapy based on a powerful immune mechanism that has not been used to fight cancer - natural antibodies.

Antibodies are proteins that the immune system produces to neutralize invaders. "In the new study, we showed that, surprisingly, antibodies are created not only in response to a threat from the outside, such as a bacterium or virus, but also in response to an internal threat in the form of cancer cells," says Prof. Ziv Shulman who led the research team alongside Prof. Irish Sagi. "These natural antibodies probably have an unrealized healing potential that must be further investigated if we want to develop new diagnostic methods or treatments for cancer," explains Prof. Sagi.

In recent years, evidence has multiplied for the presence of antibodies in cancerous tumors, but it was not clear what their purpose was and whether they were related to the cancer condition at all. Indirect evidence pointed to the possibility that the antibodies contribute to dealing with cancer: it was found that the chances of survival are improved in patients whose tumors had high concentrations of B cells - the antibody producers of the immune system. However, it was not known whether and how these cells are involved in the body's response to the tumor.

An opportunity to investigate these questions opened with the joining of Dr. Roi Mazor as a doctoral student in the laboratories of Prof. Shulman in the Department of Immunology and Prof. Sagi in the Department of Biological Control. The research journey, which lasted about six years, started with obtaining tissue samples from ovarian cancer patients, thanks to the collaboration with Prof. Ram Eitan from the Rabin Medical Center (Bilinson). Dr. Mazor and his research partners grew the cancerous tissues in the laboratory and discovered that antibodies from the patient attack the cancer and bind to the tumor cells in a precise manner. Later, the researchers sequenced the DNA of the B cells removed from the tumors and revealed the genetic segments responsible for the production of the antibodies. Moreover, among the thousands of proteins in the cancer cell, the researchers identified one specific protein to which the antibodies bind: the enzyme MMP14 (MT1-MMP) from the protease family. This enzyme acts as a kind of molecular scissors and is found in the cell membranes, is used to reshape tissues, for example during tissue regeneration or wound healing, but in a cancer tumor it goes out of control and helps malignant cells to invade neighboring tissues, spread to distant organs and form metastases.

The researchers saw that the attachment of the antibodies to the enzyme - which was found in abnormal levels in the cancer samples - causes some of them to undergo a type of evolution: they accumulate mutations that improve their attachment to the tumor, that is, to the enzyme. "We did not expect to find this kind of evolution in cancer," says Prof. Shulman. "Such changes usually occur in infectious diseases, when the antibodies accumulate mutations that help them fight bacteria or viruses, but the cancer is not a foreign invader but part of the patient's own tissue. Antibodies attacking body tissues is a worrying scenario we know from autoimmune diseases, but in this case it is probably a desirable scenario that may be useful in the fight against cancer."

Still, if the antibodies bind so effectively to the tumor, why don't they eliminate the cancer altogether? Prof. Sagi explains that the reason may lie in a prosaic matter: the fatigue of the immune system. "While protection against infection lasts for several days, a cancerous tumor develops over months and even years. After such a long battle with cancer, the immune system may be too exhausted to provide all the fighting means required to eliminate the tumor, for example, cells called 'natural killers' (NK)". Prof. Shulman adds: "We showed that the antibodies do attack the tumor, but in order to deliver a death blow, additional cells are needed to use them." As hypothesized, very low concentrations of NK cells were found in the cancer samples, but when the cells were added to the culture alongside the antibodies, they proved to be excellent assassins.

The new findings mark a new direction for cancer treatments: the use of natural anti-cancer antibodies. Although genetically engineered antibodies are already used medically today, for example to help transport T cells to a tumor as part of immunotherapy, these are synthetic antibodies. It is possible that the new approach will make it possible to use natural antibodies for this purpose in a way that will be more effective. It may also allow the use of these antibodies as a drug on its own, in combination with other treatments, or for the early diagnosis of cancer. Although the study focused on ovarian cancer, the scientists showed that the findings are also relevant to other types of cancer.

Nachum Natan, Dr. Liat Stoler-Barak, Lehi Moss, Yelin Divinsky, Dr. Merav Shmoeli, Dr. Hadas Hezroni, Dr. Irina Zaretsky, and Dr. Yifat Marble from the Institute's Department of Immunology participated in the study; Dr. Ina Solomonov and Asaf Hanona from the Department of Biological Control of the Institute; Amit Gilboa and Prof. Gur Yaari from Bar-Ilan University; Ofra Golani from the Department of Life Science Research Infrastructures of the Institute; Dr. Gad Sabah, Dr. Ariela Jacobson-Siton, Dr. Natalia Yanichkin, Prof. Maura Feinmesser, Dr. Dalia Zurf, Dr. Lina Salman, Dr. Efi Yehoshua, Eyal Peretz and Ina Erlich Center Medical Rabin; Michael Moore, Dr. Natalia Freund and Prof. Yonatan (Johnny) Gershoni from Tel Aviv University; and Dr. Neta Mendelson from the department of computer science and applied mathematics of the institute.

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