Ovarian cancer study identifies key genes for potential treatments

Graphical abstract of Ovarian Cancer diagnosis
Graphical abstract of Ovarian Cancer diagnosis

New research supported by NIHR Imperial BRC is increasing our understanding of why some women with the most fatal form of ovarian cancer respond better to treatment than others.

Researchers have confirmed that the tumours of some women with high-grade serous ovarian cancer (HGSOC) contain a type of lymphoid tissue – known as tertiary lymphoid structures (TLS) – and that the presence of this tissue gives women a significantly better prognosis. They have also identified genes in HGSOC that are important for TLS formation and function. This study is one of the first where scientists have found TLS in women with HGSOC and linked them to a better outcome.

The lymphatic system in our bodies helps fight off infection by producing immune cells such as T cells and antibodies. But TLS, which is in some ways similar to ‘normal’ lymphatic tissues, is being found by researchers in different types of tumours.

By analysing tumours from 242 HGSOC patients at Hammersmith Hospital, part of Imperial College Healthcare NHS Trust, before treatment and comparing them to progression-free survival rates, the researchers found that women that had TLS in their tumours had a significantly better outcome.

Lead researcher Dr Haonan Lu, from the Department of Surgery and Cancer, said: “People tend to think of all cancer cell activity as purely malignant – but the reality is less clear-cut. Tumours 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.”

Approximately 7,500 women are diagnosed with HGSOC each year, and because it is often discovered late, many patients experience disease relapse, leading to a five-year survival rate of below 40 per cent. It’s presently treated with surgery and chemotherapy.

Identifying genetic mutations

The team pinpointed the relevant genetic mutations involved in the cancer’s TLS formation, some of which are known to have immune-suppressing functions. The researchers found that copy number mutations in the genes IL15 and CXCL10 in HGSOC can inhibit lymphoid tissue forming. They also found that another set of genes, including DCAF15, plays a role in interacting with the TLS tissues after they have been formed, probably making them more or less active.

Dr Lu said: “There is great potential for targeting these genes for benefits in ovarian cancer treatment. It’s now becoming clear how the genetic background of the tumour type interacts with a TLS to have more or less TLS function, and that will help us identify potential targets for therapy.”

New CT scan method

The researchers have also, for the very first time, developed a potential method of identifying patients with high levels of TLS from standard CT scans, using artificial intelligence. This could ensure that those women who would benefit from different treatments are found more quickly.

Although CT scans form part of the standard treatment of the condition, TLS tissues are not visible to the human eye from a standard CT scan. But the research team has developed an artificial intelligence algorithm that was trained to detect the structures within the tumours and has successfully tested the algorithm on scans of patients at Hammersmith Hospital, known to have TLS tissues.

Professor Eric Aboagye, Professor of Cancer Pharmacology & Molecular Imaging at Imperial College London, said: “This non-invasive identification test means that oncologists will be able to determine if a patient has high or low TLS in future and treat them accordingly.”

The researchers have now received a project grant from Target Ovarian Cancer to further investigate the relevant genetic mutations identified, and explore whether it’s possible to activate anti-tumour immunity for all HGSOC patients, even those without TLS in tumours.