Genes identified that may lead to treatment for aggressive ovarian cancer
High-grade serous ovarian cancer is not only common but an aggressive, hard-to-treat type of ovarian cancer. A new study has identified the genes involved in forming a particular type of lymphatic tissue which, if growing in tumors, is associated with a better prognosis. The findings may lead to more effective, targeted treatments in the future.
Despite advances in immunotherapy, some cancers, such as high-grade serous ovarian cancer (HGSOC), respond poorly to it. HGSOC is the most common type of ovarian cancer and has the lowest survival rates, with less than 35% of women with advanced forms of the cancer surviving five years after diagnosis.
The lymphatic system helps our bodies fight infection by producing immune cells. Tertiary lymphoid structures (TLSs) are formations at persistent inflammation sites, including cancer tumors. They’re classified as ‘ectopic’ organs because they develop in non-lymphoid tissue; they appear where they wouldn’t ordinarily appear. TLSs are comprised mainly of antibody-producing B cells, cancer-fighting T cells and myeloid dendritic cells, which boost the body’s immune response. Often, inside tumors, T cells become exhausted due to persistent antigen stimulation, losing their ability to fight cancer cells.
A new study by researchers at Imperial College London has uncovered the genes that control TLS growth, which has been associated with a better prognosis in HGSOC.
The researchers analyzed tumors from 242 patients with HGSOC prior to them receiving treatment and compared them to ‘progression-free’ survival rates, that is, the length of time during and after cancer treatment that a patient lives with the disease without it getting worse. They found that women with TLSs in their tumors had significantly better outcomes. It’s one of the first times that TLSs have been linked to outcomes in women with HGSOC.
The researchers found that the TLS could proliferate and activate both B cells and T cells and that tumors high in TLSs produced a distinct population of cytotoxic T cells, tumor-destroying cells, compared to those with low TLSs.
“People tend to think of all cancer cell activity as purely malignant – but the reality is less clear-cut,” said Haonan Lu, lead author of the study. “Tumors can hijack a number of normal body processes and here, they seem to be hijacking the formation of normal human lymph tissue within themselves. Some of these lymphoid structures are able to then mature and activate T cells, which could attack the cancer itself.”
The researchers also identified the relevant genetic mutations involved in the formation of TLS within the HGSOC tumor, some of which are known to have immune-suppressing functions. They found that mutations in the genes IL15 and CXCL10 – often deleted in cancers – inhibited lymphoid tissue formation. And that another set of genes, including DCAF15, interacted with the TLS after they’d been formed, probably making them more or less active.
Identifying these genes and their interaction with TLSs could lead to more effective, targeted treatments for ovarian cancer.
“There is great potential for targeting these genes for benefits in ovarian cancer treatment,” Lu said. “It’s now becoming clear how the genetic background of the tumor type interacts with a TLS to have more or less TLS function, and that will help us identify potential targets for therapy.”
In addition to this discovery, the researchers, for the first time, developed a potential method of identifying patients with high levels of TLS using computed tomography (CT) imaging enhanced by AI. A regular CT scan will not identify TLS tissue, but the researchers trained an AI algorithm to detect the tissue within tumors. This novel detection method would ensure that women with TLSs could be identified earlier, and their treatment tailored accordingly.
Further research is needed to explore the direct impact of TLSs on T cell- and B cell-mediated anti-tumor immunity.
The study was published in the journal Cell Reports Medicine.
Source: Imperial College London