The rise of tumor immunotherapy has brought new hope to the majority of cancer patients and has become one of the most potential tumor treatment methods at present. The therapy relies on recruiting and activating the patient's own immune system, prompting the body to destroy cancer cells faster, more powerfully and more targetedly.
Unfortunately, immunotherapy is not effective for all cancer patients, in large part because we don't know enough about the immune system. If the human immune system is likened to an arsenal, existing immunotherapies are still far from exploiting the full potential of this arsenal.
In fact, most existing immunotherapies rely on an immune defense — the ability of T cells to fight tumors. However, a new study shows that B lymphocytes in cancer patients can produce natural antibodies against tumors, pointing a new direction for immunotherapy.
Recently, researchers at the Weizmann Institute of Science in Israel published a research paper entitled: Tumor-reactive antibodies evolve from non-binding and autoreactive precursors in Cell, a top international academic journal.
The study confirmed that B lymphocytes in cancer patients can produce natural antibodies specifically targeting tumors, and this new tumor immunotherapy paves the way for the use of this different, never-before-used immune system weapon , natural antibodies.
In the past few years, scientists have found natural antibodies in tumor tissue, which are likely produced by the body and have nothing to do with cancer. However, indirect evidence suggests that these natural antibodies do provide some sort of anti-tumor benefit. For example, patients who live longer than others and are more sensitive to anti-cancer drugs were found to have a higher number of B cells in their tumors that produced antibodies.
However, with this evidence alone, there is still no way to determine whether these cells and the antibodies they produce help improve survival in tumor patients, and even if this benefit does exist, how do they achieve this feat?
The Ziv Shulman lab has been working on the nature and function of B cells, while the Irit Sagi lab has expertise in creating cellular models of aggressive cancers and studying antibody mechanisms in vivo. To detect antibody targets in cancer, the two experiments collaborated to study dozens of ovarian cancer samples provided by Professor Ram Eitan of The Labin Medical Center in Israel.
After six years of research, the research team demonstrated that natural antibodies in tumor tissue targeted attacks on tumor cells and precisely bind to tumor molecules. The researchers sequenced the genomes of B cells within the tumor and identified different gene fragments that code for antibodies that bind to the tumor.
Tumor-reactive antibodies and IgG+ antibody-secreting cells (ASC) are often detected in solid tumors
The team found that these ovarian cancer samples contained unusually high levels of the MMP14 enzyme, a key membrane-binding protease. In normal people, this scissor-like enzyme plays an important role in regeneration or wound healing. In cancer patients, however, MMP14 is out of control, cutting the matrix around the cancer cells, thereby helping the cancer cells invade the surrounding tissues and spread to other organs, causing tumor metastasis.
Some antibodies undergo a variety of evolutions as the immune system attacks MMP14: they accumulate mutations that improve their adaptability to tumors, especially to this enzyme.
Professor Ziv Shulman said we did not expect such an evolution to occur around tumor tissue. These changes usually occur in infectious diseases, where antibodies gradually acquire mutations that help them better eliminate pathogens. But cancer is part of a patient's own tissue, or tissue called 'self' in the immune system.
Autoantibodies against the MMP14 enzyme are present in the tumor tissues of patients with ovarian cancer
But in any case, the fact that these antibodies target an enzyme of the body's own is surprising in itself. Because the immune system's attacks on human tissues are often harmful, they can lead to autoimmune diseases. However, for cancer, this process is clearly beneficial, and it is equally puzzling why this beneficial process does not kill the tumor.
Professor Irit Sagi said one potential cause could be the failure of the immune system. Cancer takes months or even years to develop, and after battling cancer for so long, the immune system may be exhausted to provide the full arsenal it needs to effectively kill the tumor. For example, in addition to antibodies, natural killer cells (NK Cells) are needed to achieve this goal.
The combination of natural killer cells and natural antibodies can quickly kill cancer cells
In fact, the researchers found that in tissue samples taken from ovarian cancer patients, although there were a certain number of natural antibodies, there were very few natural killer cells. When they add natural killer cells and natural antibodies to a tumor cell culture, natural killer cells can kill tumor cells very quickly.
Study pattern diagram
These findings open up a new avenue for cancer immunotherapy — taking full advantage of natural anti-tumor antibodies. These natural antibodies may help to discover previously unknown targets on tumor cells, allowing immunotherapy to target these targets more effectively. In addition, these natural antibodies may also aid in the early detection or diagnosis of cancer, and can also be developed as drugs for use alone, or in combination with other therapies.
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Thesis link: https://doi.org/10.1016/j.cell.2022.02.012
Source | Biological world