Brazilian researchers have taken an important step toward precision medicine by identifying four genes that can predict which melanoma patients will not respond to immunotherapy. Although this treatment has revolutionized the fight against melanoma, the most aggressive and lethal form of skin cancer, it is still costly and variable in efficacy, which limits its use, especially in the SUS (Sistema Único de Saúde), the country's national public health system. The goal is to use this finding to create ways to identify patients who are eligible for treatment, thus reducing costs in the public health system.
Melanoma accounts for only about 4% of skin tumors, but it is the most dangerous due to its high ability to spread to other organs. According to the National Cancer Institute (INCA), there are approximately 9,000 new cases and 2,000 deaths from melanoma in Brazil each year. For some time, it has been known that melanoma is highly immunogenic, meaning it responds well to immunotherapy, which stimulates the immune system to recognize and attack cancer cells.
PD-1 protein blockade is the standard treatment for advanced melanoma among the different types of immunotherapy. However, 40% to 60% of patients do not respond well to this approach and may experience significant side effects. This presents clinical and economic challenges, particularly in countries like Brazil, where access to immunotherapy through the public health system is limited. Although the National Commission for the Incorporation of Technologies (CONITEC) has recommended including it in the public health system, the high cost still prevents routine adoption of the treatment.
The study
Against this backdrop, biotechnological engineer Bruna Pereira Sorroche decided to investigate the possibility of identifying genetic markers that could predict the effectiveness of immunotherapy for individuals with melanoma. Funded by FAPESP through two projects ( 19/07111-9 and 19/03570-9 ), the study was conducted at the Molecular Oncology Research Center of Hospital de Amor (formerly Barretos Cancer Hospital) in the interior of the state of São Paulo under the guidance of Professor Lídia Maria Rebolho Batista Arantes . The results were published in the Journal of Molecular Medicine.
The study examined tumor samples from 35 patients with advanced melanoma who were treated with anti-PD-1 immunotherapy at Hospital de Amor between 2016 and 2021. The scientist cross-referenced these samples with data from a panel of 579 immune system-related genes. She identified four genes – CD24, NFIL3, FN1, and KLRK1 – whose increased expression was strongly associated with treatment resistance.
According to the study, patients with high expression of these genes were 230 times more likely to not respond to immunotherapy than those with low expression. Additionally, overall survival was lower in cases of high gene expression: after five years, 48.1% of patients with low gene expression were still alive, compared to 5.9% of those with high expression.
An in-depth analysis revealed that these genes are associated with mechanisms of immune evasion and the suppression of the inflammatory response. For instance, the CD24 gene acts as an immune checkpoint, enabling tumors to evade the body's defense system. FN1 is associated with tumor progression and the formation of structures that promote cancer growth. KLRK1 is typically involved in activating immune cells but can lose its function when dysregulated, which weakens the body's response to the tumor. The NFIL3 gene plays an important role in the immune response and may contribute to tumor escape.
"The increased expression of these four genes is related to known mechanisms of tumor development and immune escape – that is, ways in which cancer manages to 'hide' from the body's defense system. This would explain why some patients do not benefit from immunotherapy, even when treatment is technically indicated," Sorroche says.
To validate the findings, the team compared the results with data from two independent, international cohorts. The genetic signature was still effective at predicting treatment response and clinical outcomes, despite the expected variations between the analyzed groups. One unique feature of the study was its use of NanoString technology. This genetic analysis platform is more accessible and cost-effective than traditional RNA sequencing. It can be applied in clinical practice, including in hospitals with fewer resources.
Another promising aspect is that this genetic signature has also proven to be predictive in patients diagnosed in the early stages of the disease. This suggests that a tumor's genetic profile could be useful from the beginning of treatment to help make more effective therapeutic decisions.
The team is in the process of patenting the technology. The idea is to create a panel that uses these and other genes as a commercial tool to assess whether a patient has a real chance of benefiting from immunotherapy before treatment is recommended. "This can help doctors and healthcare managers decide on the best therapeutic path, avoiding unnecessary expenses with a treatment that can cost between BRL 30,000 and BRL 40,000 per month [approximately between 5,400 and 7,200 dollars], an amount that's impractical for most patients and also for the SUS, especially if the treatment lasts for years," comments Arantes, the study's advisor.
Although the research was conducted with a small number of patients and retrospective data, Sorroche and Arantes believe the findings offer a promising path toward personalized melanoma treatment. This could spare patients from the side effects of ineffective therapies and help allocate public resources more efficiently. "Our finding is unprecedented because the research was based on the genetic profile of the population served by the SUS, which ensures greater adherence to the realities of public health in Brazil," Arantes says.
The next step is to conduct larger studies to validate the results and define a cutoff value – that is, the minimum level of gene expression above which a positive response to treatment would be unlikely. This panel could then be used as a predictive tool to help doctors make more informed decisions about the therapeutic approach offered to each patient. This initiative could be a turning point for personalized oncology in Brazil.
About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.
