A study by Sant Joan de Déu identifies the mechanisms that hinder the effectiveness of treatment for diffuse intrinsic pontine glioma in children

Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive and lethal childhood brain tumors, with an annual incidence of between 20 and 30 cases in Spain. With an average life expectancy of less than two years after diagnosis and no curative treatments available, research into this type of cancer is key to advancing new therapeutic strategies.

A team of researchers led by Ángel Montero Carcaboso, head of the pediatric cancer treatment group at the Institut de Recerca Sant Joan de Déu (IRSJD), published the article Proteins of the cancer cell secretome induce the protumoral microenvironment of diffuse intrinsic pontine glioma in the journal Neuro-Oncology Advances, identifying mechanisms that allow DIPG to evade the immune system and thrive in the pediatric brain, preventing treatment effectiveness.

The study results show that tumor cells secrete two proteins -osteopontin and chitinase-3-like 1 (CHI3L1)- that profoundly alter the surrounding cellular environment, promoting an immunosuppressive and pro-tumoral microenvironment.

The study demonstrates that these proteins alter the behavior of several normal brain cell types to favor the tumor environment. They cause certain stem cells (mesenchymal) to transform into cells that suppress the immune response, helping the tumor evade the body's defenses. They also strengthen blood vessels and the brain's blood-brain barrier, making treatment access to the tumor nearly impossible. Additionally, they cause macrophages -a type of defensive cell- to adopt an anti-inflammatory role, typical of environments that promote tumor growth.

Montero highlights that "this study has discovered that DIPG cells not only grow aggressively, but actively create an environment that disables the body's defenses. Understanding this mechanism offers the opportunity to develop new strategies to break the protective shield generated by the tumor."

Researchers reached these conclusions by analyzing brain tissue, cerebrospinal fluid, and blood samples from DIPG patients, and conducting in vitro experiments with human cells and animal models. The presence of these two proteins in patients' cerebrospinal fluid also opens the possibility of using them as non-invasive biomarkers.

This work expands knowledge about the tumor microenvironment of DIPG and reinforces the need to develop personalized immunotherapy strategies, aimed at counteracting the action of these proteins or reversing the changes they induce.

Tissue donation and financial resources

The study was made possible thanks to the altruism of 35 families who donated brain tissue samples from their children, both DIPG patients and children without tumor pathologies. According to Montero, "this generous donation enabled a very precise and comparative analysis of the tumor environment, essential to understand how DIPG modifies its microenvironment to grow and resist the immune system." Additionally, families affected by the tumor created associations that have continuously and selflessly funded this research.

Sample collection was made possible thanks to the work of the Sant Joan de Déu Hospital Biobank, which for more than 10 years has tracked, managed, and preserved samples from DIPG patients as well as non-tumoral brain tissue, providing a unique foundation for biomedical research in this field.

Future perspectives

Alongside this research, Sant Joan de Déu Hospital is opening promising avenues for the development of treatments against DIPG. Among the ongoing strategies is the design of a clinical trial combining dendritic cells and CAR-T therapy to activate the immune system and target tumor cells. Another initiative will be a trial led by the spin-off Gate2Brain, based on an innovative technology that allows crossing the blood-brain barrier and facilitating drug delivery to the brain.

Both initiatives respond to the urgent need to find new therapeutic options to combat this type of tumor, which currently still has a very limited prognosis.

The study involved various research groups from the Institut de Recerca Sant Joan de Déu (IRSJD), as well as collaborators from the Josep Carreras Leukemia Research Institute (IJC), the Biomedical Research Networking Center in Oncology (CIBERONC), ICREA, the Polytechnic University of Catalonia (UPC), the Hospital Clínic de Barcelona and the SJD Barcelona Children’s Hospital.

The study was funded by the Instituto de Salud Carlos III, FEDER funds, and the Departament de Salut of the Generalitat, under its PERIS 2018-2020 program.