Tuesday, December 10, 2013

Pediatric Brain Tumors Exhibit Distinct Phenotypes: Should Therapies Be Individualized?

Tumors are never something to joke around about; they are dangerous, unpredictable, and they can even be fatal. They can appear nearly anywhere in the human body, at basically any point in time. In fact, one of the most dangerous habitats for a tumor is the brain. A complicated and mysterious part of the human body already, the brain controls almost everything, and a tumor appearing in this region can be devastating. They are difficult to remove, and they can have disastrous mental and physical consequences. Even worse, they can present themselves at any age. This makes children susceptible, and what could be worse than that? With around 1,500 children diagnosed a year, pediatric brain tumors are not the most common cause of death in children (1). However, they are the most common type of pediatric tumor, and they have the highest mortality rate over all other childhood cancers. Despite its reputation, this deadly disease has had no improvements regarding treatment methods in the past. Until recently even, the standard treatment was radiation exposure and chemotherapy, which were often coupled with horrible, debilitating side effects. Now, a new form of treatment has been devised due to its tumor specificity – immunotherapy.

"Types of Brain and Spinal Cord Tumors in Children." Johns Hopkins Medicine.
Johns Hopkins University, Hospital, and Health System, 2013. Web. 10 Dec. 2013.
Studies have shown that there have been positive correlations between host immunity and survival rate in children diagnosed with brain tumors. Still, immunotherapy has demonstrated to be largely ineffective due to the immunosuppression induced by brain tumors because it tampers with the immune system-supressing qualities of the exogenous therapy. Several scientists researched pediatric brain tumor types further, however, in order to better understand immunophenotypes – the immunological characteristics – of these tumors. They hoped to shed some light on the subject in order to be able to better treat these afflicted children and give them more of a fighting chance.
In Andrea Griesinger and her colleagues’ study, they measured the phenotype and frequency of tumor-infiltrating leukocytes in the four most common types of child brain tumors*(4). They began by surgically taking tumor samples from forty-two patients at the Children’s Hospital in Colorado; they also took five non-tumor samples for a control group. Then, the tissue samples were disaggregated and frozen, before they were eventually suspended, stained, and analyzed via a FACS analysis and a gene expression analysis (2, 3). The FACS analysis then sorted the variety of cells into two or more containers based on their fluorescence while the gene expression analysis quantified the expression levels of certain genes.
In their results, Griesinger and the other scientists found that the amount of infiltration, or migration, of certain cells to the tumors heavily depended on the type of tumor. Myeloid cells were mostly found in pilocytic astrocytomas (PA) or ependymomas (EPN), for example. These myeloid cell phenotypes were also more activated in PA and EPN, and the activation markers were higher in prevalence as well. Similarly, T cells were found to be distributed like myeloid cells, but they were less common. CD8+ and CD4+ T cells greatly varied between tumor cell types as well. Overall, however, after analyzing everything in their data the scientists founds that each type of tumor had a distinctive immunophenotype, emphasizing the uniqueness of each particular pediatric brain tumor.
Previous studies have focused primarily on the adult form of glioblastoma (GBM), and many findings on tumors have taken knowledge from GBM research without realizing that GBM phenotypes may not be applicable to other tumor types. PA and EBN display more leukocyte infiltration than any of the other tumors tested, for example, and medulloblastoma (MED) had far less leukocyte infiltration than the other tumors. The importance of this information cannot be lost on the details, however. These infiltrating leukocytes that were studied signify sources of endogenous cells that can be utilized by the immune system. This is where the immunotherapy comes in. The three types of immunotherapies – passive, adoptive, and active – could be utilized for different types of brain tumors, depending on the levels of certain cells in the tumors and what phenotypes were more activated and where. Thus, these findings will hopefully help in figuring out the specifics for treatment of pediatric brain tumors, improving immunotherapeutic approaches all the while discouraging the more damaging chemotherapeutic treatment.
*Brain Tumors Studied: Pilocytic Astrocytoma, Ependymoma, Medulloblastoma, and Glioblastoma.

Primary Article:

Griesinger, Andrea M. et. al. 2013. Characterization of Distinct Immunophenotypes across Pediatric Brain 
               Tumor Types. Journal of Immunology. 191: 4880-4888.

Other Articles:
4. http://www.cbtf.org/learn/what-brain-tumors-are-common-i

"Types of Brain and Spinal Cord Tumors in Children." Johns Hopkins Medicine. Johns Hopkins University, Hospital, and Health System, 2013. Web. 10 Dec. 2013.

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