A study conducted by the Molecular Oncology Research Centre (CPOM) at Hospital de Amor in Barretos (formerly Barretos Cancer Hospital) in the state of São Paulo, Brazil, has identified possible biomarkers that could guide the development of more personalised therapies for paediatric germ cell tumours (GCTs).

Although GCTs account for only 3% of childhood cancers, they challenge doctors and researchers due to their diversity and the toxicity of available treatments.

The main approach today involves surgery combined with chemotherapy.

While effective in many cases, this protocol is not equally effective for all tumour subtypes and can cause long-term side effects.

For this reason, researchers at Hospital de Amor decided to investigate the “immune environment” of GCTs.

In other words, they aimed to understand how a patient’s immune cells interact with tumour cells.

Their goal was to identify patterns explaining why some tumours are more aggressive than others and to identify new therapeutic targets, especially those linked to immunotherapy.

“Germ cell tumours can occur in adults as well as children and adolescents. In the paediatric population, they’re very rare, accounting for about 3% of tumours. Due to their rarity and heterogeneity, they’re difficult tumours to study,” explains Mariana Tomazini, study advisor and researcher at the CPOM.

According to Tomazini, GCTs can arise in different locations, including the ovaries, testicles, central nervous system, and retroperitoneum.

They can also present as different histological types, which are variations in cellular appearance and growth pattern.

“It’s like a ‘signature’ of the tumour, a surname. This is because within the same organ, we can have tumours with different characteristics. This subtype, or histological type, helps doctors define the diagnosis and choose the best treatment strategy,” says Tomazini.

The research, which was funded by FAPESP (projects 19/07502-8 and 23/07073-5), was conducted as part of Lenilson Silva’s master’s project.

Silva analysed samples from 17 paediatric patients diagnosed with germ cell tumours between 2000 and 2021.

Of those, 11 were ovarian, three were testicular, and three were in the central nervous system.

Four normal, tumour-free tissues were also used for comparison.

The results were published in the journal Frontiers in Immunology.

The scientists evaluated the expression of approximately 800 immune system-related genes and the presence of different types of immune cells infiltrating the tumours based on the tissue samples.

They then compared these data with gene expression data from adult tumours in public databases, looking for similarities and differences between age groups.

Tomazini explains that the goal was precisely to understand how the immune system behaves in each type of tumour.

“From this analysis, we saw that different histologies have a distinct immune profile. This helps to better characterise the tumour, understand why some are more aggressive, and, at the same time, identify possible therapeutic targets. It paves the way for future studies focused on immunotherapy,” she says.

Distinct immunological profiles

The study revealed that each tumour subtype has its own immune profile, acting as a “biological signature” that can influence clinical behaviour and response to treatment.

For example, the microenvironment of dysgerminomas (ovarian tumours) proved to be “immunologically active,” with a significant presence of T lymphocytes, particularly CD8⁺ cells, which can attack diseased cells.

Conversely, these tumours exhibited an increase in immune checkpoint molecules, including CTLA-4, TIGIT, and IDO1, which hinder the immune response.

This suggests that dysgerminoma may respond well to immune checkpoint inhibitors, which are already used to treat some adult cancers, such as melanoma and lung cancer.

“This histological type, for example, had a higher number of cytotoxic T cells. This explains why it’s usually a less aggressive tumour with a good response to treatment and active defences in the body,” the researcher comments.

Endodermal sinus tumours (yolk sac tumours, or YSTs), on the other hand, exhibited a more immunosuppressive environment.

Their T lymphocytes were exhausted and less efficient at fighting the tumour.

Additionally, they had high levels of CD24 and PVR, which are molecules associated with immune evasion and resistance to chemotherapy.

These molecules are also linked to more aggressive tumours.

“In this subtype, the defence cells recognise the tumour but are unable to act as effectively. This helps explain why YSTs are more aggressive,” Tomazini explains.

An increase in CD24 was also observed in another subtype analysed, embryonic carcinomas.

Previous studies have suggested that blocking CD24 could help restore sensitivity to chemotherapy.

“CD24 was a major finding. It’s been studied as a tumour cell marker in different cancers. If we can block its action, we may be able to reduce tumour progression or even facilitate the immune system’s recognition of diseased cells,” Tomazini celebrates.

Mixed tumours of the central nervous system, on the other hand, showed fewer significant changes, which may be linked to cellular diversity or the reduced number of samples.

Why does it matter?

The results show that each subtype of germ cell tumour in children has its own immune signature.

According to the scientist, this finding paves the way for more individualised treatments.

“This means that it’s useless to apply the same generic treatment to all GCTs. Each patient has a tumour with a distinct immune profile. And, because we’re dealing with children, the more options that are less aggressive and have fewer long-term side effects, the better,” the researcher argues.

Because it is a rare cancer, the study involved only 17 patients, a small number in statistical terms.

Additionally, not all histological subtypes were represented.

Nevertheless, the results are considered a pioneering first step.

The group intends to validate the findings in multicenter studies with a larger number of samples and move forward with clinical trials testing specific immunotherapies for the different subtypes.

“This is the key issue in our study: the search for new biomarkers that can identify germ cell tumours and their subtypes in order to achieve a more accurate and specific diagnosis. Then, we can consider more appropriate targeted therapies or immunotherapies. Knowing what differentiates each tumour allows us to consider personalised treatments that are more effective and less toxic for children,” Tomazini concludes.

The study won the award for best paper at the Latin American Society of Paediatric Oncology (SLAOP) conference held in Colombia this year.

The event promotes interdisciplinary scientific development in paediatric oncology and haematology, as well as improving standards of care and clinical development for children and adolescents with cancer.

Source: Fundação de Amparo à Pesquisa do Estado de São Paulo