Cell: Natural antibodies exist in cancer patients' tumors, opening up new directions for cancer treatment

The rise of tumor immunotherapy has brought new hope to the majority of cancer patients and has become one of the most promising tumor treatments at present
.

The therapy relies on recruiting and activating a patient's own immune system, prompting the body to destroy cancer cells faster, more powerfully and in a more targeted manner

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 one immune defense—the ability of T cells to fight tumors
.

However, a new study has shown that B lymphocytes of cancer patients can produce natural antibodies against tumors, pointing out a new development direction for immunotherapy

B lymphocytes of cancer patients can produce natural antibodies against tumors, indicating a new development direction for immunotherapy

Cell Tumor-reactive antibodies evolve from non-binding and autoreactive precursors

The study confirms that B lymphocytes of cancer patients can produce natural antibodies that specifically target the tumor, paving the way for a new tumor immunotherapy that promises to use this different and never before used weapon of the immune system - natural antibodies
.

It is expected to use this different and never before used weapon of the immune system - natural antibodies
.

It is expected to use this different and never before used weapon of the immune system - natural antibodies

Over the past few years, scientists have discovered natural antibodies in tumor tissue that are likely produced by the body and have nothing to do with cancer
.

However, indirect evidence suggests that these natural antibodies do provide some antitumor benefit

However, this evidence alone is still no way to determine whether these cells and the antibodies they produce help improve the survival of cancer patients, and if such benefits do exist, how do they achieve this feat?

Ziv Shulman's lab has been working on the nature and function of B cells, while Irit Sagi's 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 on dozens of ovarian cancer samples provided by Professor Ram Eitan of the Rabin Medical Center in Israel

After six years of research, the research team has demonstrated that natural antibodies in tumor tissue target tumor cells and bind precisely to tumor molecules
.

The researchers sequenced the genomes of B cells within the tumor and identified distinct gene segments that encode antibodies that bind to the tumor

Natural antibodies in tumor tissue target tumor cells and bind precisely to tumor molecules

Tumor-reactive antibodies and IgG+ antibody secreting cells (ASCs) are frequently detected in solid tumors

Tumor-reactive antibodies and IgG+ antibody secreting cells (ASCs) are frequently detected in solid tumors

The team found that these ovarian cancer samples contained abnormally high levels of the enzyme MMP14, a key membrane-bound protease
.
In normal people, the scissors-like enzyme plays an important role in regeneration or wound healing
.
In cancer patients, however, MMP14 is out of control, cleaving the stroma surrounding cancer cells, thereby helping cancer cells invade surrounding tissues and spread to other organs, leading to tumor metastasis
.

During the immune system's attack on MMP14, some antibodies have undergone a variety of evolutions: They have accumulated mutations that have improved their fitness against tumors, particularly the enzyme
.

They accumulated some mutations that improved their fitness for tumors, especially for this enzyme
.
They accumulated some mutations that improved their fitness for tumors, especially for this enzyme
.

Professor Ziv Shulman said that we did not expect such an evolution to occur around tumor tissue
.
These changes typically occur in infectious diseases, where antibodies gradually acquire mutations that help them better destroy pathogens
.
But cancer is part of a patient's own tissue, or what is called 'self' in the immune system
.

Autoantibodies against MMP14 enzyme exist in tumor tissue of ovarian cancer patients

Autoantibodies against MMP14 enzyme exist in tumor tissue of ovarian cancer patients

But in any case, the fact that these antibodies target one of the body's own enzymes is surprising in itself
.
Because the immune system's attack on the body's tissues is often harmful, it can lead to autoimmune diseases
.
For cancer, however, 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 a breakdown of the immune system
.
It takes months or even years for cancer to develop, and after battling cancer for so long, the immune system may be exhausted and unable to provide the full set of weapons needed to effectively kill tumors
.
For example, in addition to antibodies, natural killer cells (NK Cells) are required for this purpose
.

Combined use of natural killer cells and natural antibodies can rapidly kill cancer cells

Combined use of natural killer cells and natural antibodies can rapidly kill cancer cells

In fact, the researchers found that tissue samples taken from ovarian cancer patients had a fair amount of natural antibodies but very few natural killer cells
.
When they added natural killer cells to tumor cell cultures along with natural antibodies, the natural killer cells killed tumor cells very quickly
.

In tissue samples taken from ovarian cancer patients, although a certain number of natural antibodies were present, there were few natural killer cells
.
When they added natural killer cells to tumor cell cultures along with natural antibodies, the natural killer cells killed tumor cells very quickly
.

Research Pattern Diagram

Research Pattern Diagram

These findings open up a new avenue for cancer immunotherapy that takes full advantage of natural anti-tumor antibodies
.
These natural antibodies may help discover previously unknown targets on tumor cells, allowing immunotherapies to more effectively target them
.
In addition, these natural antibodies may also aid in the early detection or diagnosis of cancer, and may also be developed as drugs used alone or in combination with other therapies
.

These natural antibodies may also aid in the early detection or diagnosis of cancer, and may also be developed as drugs used alone or in combination with other therapies
.
These natural antibodies may also aid in the early detection or diagnosis of cancer, and may also be developed as drugs used alone or in combination with other therapies
.

 

Original source:

Original source:

Roei D.
Mazor, et al.
Tumor-reactive antibodies evolve from non-binding and autoreactive precursors.
Cell, 2022.

Roei D.
Mazor, et al.
Tumor-reactive antibodies evolve from non-binding and autoreactive precursors.
Cell, 2022.
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