News
Article
TIM3 Targeted Immunotherapy Shows Promise in Pediatric Brain Cancer
Author(s):
Breakthrough research identifies TIM3 as a key target in MAPK-activated pediatric gliomas, offering new hope for more effective immunotherapy treatments.
Despite being a leading cause of childhood mortality, pediatric gliomas remain underresearched, with immunotherapy efforts proving largely unsuccessful.1 However, investigators have identified the TIM3 protein as a promising new target for treating pediatric brain cancers, particularly in low-grade astrocytomas where current immunotherapies have been ineffective.
“This study lays the translational groundwork for a clinical trial of anti-TIM3 therapy in pediatric patients with pilocytic astrocytoma who are in dire need of therapeutic strategies,” said Michael DeCuypere, MD, PhD, assistant professor of neurological surgery in the Division of Pediatric Neurological Surgery and co–senior author of the study, in a statement.1
This cohort study is published in The Journal of Clinical Investigation.2
Pilocytic astrocytoma is low-grade brain tumor, and the most common type of brain tumor in children.1 Although most tumors can be surgically resected, patients with tumors in areas of the brain that cannot be accessed through surgery are in critical need of alternative treatment options in addition to chemotherapy and radiation.
In this study, the researchers analyzed novel pediatric glioma models to identify new therapeutic targets in pilocytic astrocytoma tumors.2
The study utilized a combination of methods to identify TIM3 as a therapeutic target in pediatric gliomas, particularly pilocytic astrocytomas. Whole transcriptome sequencing was used to analyze gene expression profiles, helping to reveal key molecular characteristics of MAPK-driven gliomas. This technique allowed researchers to identify a heightened interferon signature in these tumors, indicating an existing, albeit insufficient, immune response.
To further dissect the tumor microenvironment at the cellular level, single-cell sequencing was conducted. This method facilitated the identification of specific immune cell populations, including a unique cytotoxic microglia subset (MG-Act) present in low-grade gliomas but absent in high-grade tumors and normal brain tissue.
Additionally, the study leveraged sequential multiplex immunofluorescence to map the expression of the TIM3 protein in the tumor microenvironment. Genetically engineered mouse models of MAPK-driven low-grade gliomas were also developed to test the therapeutic potential of anti-TIM3 treatment.
Ex vivo experiments with immune cells from human pilocytic astrocytoma samples were treated with anti-TIM3 to observe changes in their behavior. ScRNA sequencing was also used to analyze changes in immune cell populations during the therapeutic window.
In preclinical mouse models of low-grade gliomas, anti-TIM3 treatment notably increased survival compared with both immunoglobulin G (IgG) and anti-PD1 therapies, which are commonly used in immunotherapy. Single-cell sequencing revealed a unique population of cytotoxic microglia, termed MG-Act, in pilocytic astrocytoma tumors, which was enriched following anti-TIM3 therapy. This microglia subset was not observed in high-grade tumors or healthy brain tissue, suggesting its specific role in low-grade gliomas.
Moreover, TIM3 expression was found on myeloid cells within the tumor vasculature, but not in normal brain tissue, highlighting its potential as a tumor-specific target. The study also showed that blocking TIM3 reprogrammed immune cells from human pilocytic astrocytoma samples into a pro-inflammatory and cytotoxic phenotype, suggesting a mechanism by which TIM3 inhibition could enhance immune activity against the tumor.
“In the high-grade tumors, the T cells are exhausted and can’t be reinvigorated with standard immunotherapy. However, in the low-grade tumors, the T cells are not exhausted to the same degree and there is baseline immune reactivity by the interferon signature,” said Shashwat Tripathi, a student in the Medical Scientist Training Program and lead author of the study.1
The therapeutic efficacy of anti-TIM3 was further supported by the finding that its activity was abrogated in CX3CR1 microglia knockout models, demonstrating that microglia play a critical role in mediating the treatment’s effects.2
These results collectively suggest that TIM3 inhibition could be a promising approach for pediatric gliomas, particularly in patients with limited treatment options.
From this study, the researchers support a clinical trial for treating pediatric brain cancer in patients with TIM3-targeted therapy.
“We would like to move this directly into a clinical trial with kids who have failed standard therapies and even more modern targeted therapies here at Lurie Children’s Hospital and Northwestern,” DeCuypere said in a statement.1
References
1. Rohman M. Investigators discover new therapeutic target for pediatric brain cancers. News release. Northwestern Medicine. August 19, 2024. Accessed September 10, 2024. https://news.feinberg.northwestern.edu/2024/08/19/investigators-discover-new-therapeutic-target-for-pediatric-brain-cancers/
2. Tripathi S, Najem H, Dussold C, et al. Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF-fusion pilocytic astrocytoma. J Clin Invest. Published online August 13, 2024. doi:10.1172/jci177413
