NEW YORK (Reuters Health) – The immune systems of ovarian cancer patients can produce antibodies against tumors, a cell-based study shows, and researchers suggest the finding could lead to a new type of immunotherapy.
“Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors,” Dr. Ziv Shulman of the Weizmann Institute of Science and colleagues write in Cell. “Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC).”
The team has generated 17 monoclonal antibodies that bind ovarian tumor cells, Dr. Shulman told Reuters Health by email. “The next step is to determine their specificity to the tumor cells and examine if they have therapeutic effects in mouse models,” he said.
“The biggest challenge is to identify the targets of the antibodies we have generated,” he noted. “We generated several antibodies based on sequences we obtained from patients. Each antibody has a target. We found 9 antibodies that bound the same tumor target (MMP14). And we have more antibodies but we do not know if any are binding on tumor cells.
In the current study, the team found that antibodies generated from immune cells within human ovarian carcinomas, as well as pre-existing autoantibodies, coat tumor cells – often with IgGs – and contribute to antitumor immune responses.
Further, the intratumoral antibody-secreting cells (ASCs) in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, as Dr. Shulman indicated. The mutations improved the cells’ fit to the tumor, and specifically to MMP14.
To examine whether the binding of patient-derived monoclonal antibodies depended on SHMs for tumor binding, the team reverted their sequence to their germline versions and tested their binding capacity to ovarian cancer cells. The investigation revealed two types of tumor-reactive antibodies in the patients: one that depends on SHMs for tumor binding (class I) and another type that binds the tumor in their germline form (class II).
The authors write, “Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.
From a clinical perspective, Dr. Shulman suggests, “The presence and amount of antibodies in the tumor might be used for prediction of therapeutic drug effects. Furthermore, one or several of the discovered monoclonal antibodies that target the tumor might be useful as new treatment for patients in the future.”
“In addition,” he said, “since we understand that antibodies are found within the tumors, treatments with cells that bind can use them for tumor killing, or attracting such effector cells might be the right treatment for patients.”
SOURCE: https://bit.ly/3u6MPCE Cell, online March 18, 2022.
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