February 23, 2024

High-grade serous ovarian cancer is not only common but also an aggressive, difficult-to-treat form of ovarian cancer. A new study has identified genes involved in the formation of a specific type of lymphoid tissue that is associated with better prognosis if this tissue grows in tumors. These findings may lead to more effective and 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 rate, with less than 35 percent of women with advanced cancer surviving five years after diagnosis.

The lymphatic system helps our body fight infection by producing immune cells. Tertiary lymphoid structures (TLS) are the formation of sites of persistent inflammation, including cancerous tumors. They are classified as “ectopic” organs because they develop in nonlymphoid tissues. They show up where they normally don’t. Consisting primarily of antibody-producing B cells, cancer-fighting T cells, and bone marrow dendritic cells, TLS boost the body’s immune response. Typically, inside tumors, T cells become exhausted from constant antigen stimulation and lose their ability to fight cancer cells.

A new study by researchers at Imperial College London has identified genes that control the growth of TLS, which is associated with a better prognosis in HGSOC.

The researchers analyzed tumors from 242 HGSOC patients before treatment and compared them to “progression-free” survival rates, or the length of time patients lived without their disease getting worse during and after cancer treatment. They found that women whose tumors contained TLS had a significantly better prognosis. This is the first time TLS has been linked to outcomes in women with HGSOC.

The researchers found that TLS can proliferate and activate both B and T cells, and that tumors high in TLS produced a distinct population of cytotoxic T cells, called tumor-destroying cells, compared with tumors low in TLS.

“People tend to think that all cancer cell activity is purely malignant, but it’s not so clear-cut,” said Haonan Lu, the study’s lead author. “Tumors can hijack many normal bodily processes, and here, they seem to hijack their own internal The formation of normal human lymphoid tissue. Some of these lymphoid structures are able to mature and activate T cells to attack the cancer itself.”

The researchers also identified mutations in genes associated with TLS formation within HGSOC tumors, some of which are known to have immunosuppressive functions. They found that mutations in the genes IL15 and CXCL10, which are often deleted in cancer, inhibit the formation of lymphoid tissue. Another set of genes, including DCAF15, interact with TLSs after they form, possibly making them more or less active.

Identifying these genes and their interactions with TLS may lead to more effective and targeted ovarian cancer treatments.

“Targeting these genes has enormous potential in ovarian cancer therapy,” Lu said. “It is now becoming clearer how the genetic background of tumor types interacts with TLS to be more or less TLS-functional, which will help us identify potential therapeutic targets.”

In addition to this discovery, the researchers have for the first time developed a potential method to identify patients with high TLS levels using artificial intelligence-enhanced computed tomography (CT) imaging. Regular CT scans cannot identify TLS tissue, but the researchers trained an artificial intelligence algorithm to detect the tissue within the tumor. This novel assay will ensure that women with TLS can be identified earlier and treatment planned accordingly.

Further studies are needed to explore the direct effects of TLS on T- and B-cell-mediated antitumor immunity.

The study was published in the journal Cell Report Medicine.

source: Imperial College London