Study identifies immune biomarkers for personalized therapies in pediatric germ cell tumors

A study conducted by the Molecular Oncology Research Center (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 personalized therapies for pediatric germ cell tumors (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 tumor 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 tumor cells. Their goal was to identify patterns explaining why some tumors are more aggressive than others and to identify new therapeutic targets, especially those linked to immunotherapy.

Germ cell tumors can occur in adults as well as children and adolescents. In the pediatric population, they're very rare, accounting for about 3% of tumors. Due to their rarity and heterogeneity, they're difficult tumors to study."

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 tumor, a surname. This is because within the same organ, we can have tumors 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 analyzed samples from 17 pediatric patients diagnosed with germ cell tumors between 2000 and 2021. Of those, 11 were ovarian, three were testicular, and three were in the central nervous system. Four normal, tumor-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 tumors based on the tissue samples. They then compared these data with gene expression data from adult tumors 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 tumor. "From this analysis, we saw that different histologies have a distinct immune profile. This helps to better characterize the tumor, 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 tumor subtype has its own immune profile, acting as a "biological signature" that can influence clinical behavior and response to treatment.

For example, the microenvironment of dysgerminomas (ovarian tumors) proved to be "immunologically active," with a significant presence of T lymphocytes, particularly CD8⁺ cells, which can attack diseased cells. Conversely, these tumors 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 tumor with a good response to treatment and active defenses in the body," the researcher comments.

Endodermal sinus tumors (yolk sac tumors, or YSTs), on the other hand, exhibited a more immunosuppressive environment. Their T lymphocytes were exhausted and less efficient at fighting the tumor. 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 tumors. "In this subtype, the defense cells recognize the tumor 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 analyzed, 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 tumor cell marker in different cancers. If we can block its action, we may be able to reduce tumor progression or even facilitate the immune system's recognition of diseased cells," Tomazini celebrates.

Mixed tumors 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 tumor in children has its own immune signature. According to the scientist, this finding paves the way for more individualized treatments. "This means that it's useless to apply the same generic treatment to all GCTs. Each patient has a tumor 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 tumors 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 tumor allows us to consider personalized 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 Pediatric Oncology (SLAOP) conference held in Colombia this year. The event promotes interdisciplinary scientific development in pediatric oncology and hematology, as well as improving standards of care and clinical development for children and adolescents with cancer.