Zika Virus as a Potential Treatment for Childhood Brain Tumors

Childhood brain tumors, especially the malignant ones like medulloblastoma and ATRT, are a big deal. They are the most common solid cancers in kids and often lead to serious health issues and even death. Treatments we have now are pretty tough and can leave patients with lasting problems, making life hard even for those who survive. There's a real need for therapies that are less harsh and more precise, especially ones that can get the immune system to fight the tumor.

One interesting approach is using oncolytic viruses (OVs). These are viruses that can specifically target and kill cancer cells, which helps reduce the need for high doses of chemotherapy and radiation – both of which are no fun. These viruses work in two main ways: they directly destroy the infected cancer cells and activate the immune system to fight back against the tumor.

#The Challenge of Aggressive Tumors

Many childhood cancers, including medulloblastoma and ATRT, have what we call "cancer stem-like cells." These little troublemakers contribute to things like tumor growth, spreading, and resistance to treatment. The good news is that OVs have shown promise in targeting these tough cells, which could help overcome treatment challenges.

To date, a handful of OVs have been approved for clinical use, and a whopping 200 clinical trials are testing them for treating various cancer types. Since 2015, interest in OV research has soared, especially with the FDA giving the green light for a modified herpes virus to treat adult melanoma. More recently, in 2022, Japan approved a herpes virus named Delytact to treat recurrent adult brain tumors.

There are also ongoing trials looking at using OVs for childhood brain tumors, with some showing promising results in improving survival rates and mostly mild side effects.

#The Zika Virus

Now, let’s talk about the Zika virus. This little bugger is a single-stranded RNA virus. It can be passed from mothers to babies during pregnancy, leading to various complications. The virus infects certain brain cells in the fetus, causing growth issues and even developmental problems. However, in older kids and adults, Zika infection often doesn't cause many symptoms and typically resolves itself in a week or so.

In our lab, we've shown that Zika can infect and kill aggressive brain Tumor Cells from kids and adults. We've seen that Zika can also promote the immune system to attack tumors without harming the brain in mouse models. The immune response includes various types of immune cells that help clear the tumor out, leading to long-lasting immunity.

Interestingly, Zika has also been shown to fight off tumors in dogs, decreasing tumor size and improving clinical symptoms without causing lasting harm.

#The Need for More Research

While we know a lot about Zika and its effects on tumors, there’s still much to learn. We need to apply modern data techniques to understand how Zika behaves in childhood brain tumor cells. Although we know that Zika affects WNT signaling, the full picture regarding the response of tumor cells versus patient-derived cells is still unclear.

In our current study, we aimed to observe how different brain tumor cells and cells from children affected by Zika reacted during the initial hours of infection. We found that the way Zika affects these cells varies widely.

For instance, the neural precursor cells from Zika-affected children show a big drop in important developmental processes following infection. This is not good news. Meanwhile, the brain tumor cells show signs of immune response activation, leading to an anti-tumor effect. We also identified a potential marker that might help predict how patients will respond to Zika treatment.

#The Impact of Zika on Tumor Cells

After infecting the tumor cells with Zika, we noticed different responses depending on the cell type. Through high-tech analysis, we found that Zika virus infection causes specific changes in the gene expression of both tumor and neural precursor cells.

Over roughly 12 to 24 hours, the tumor cells showed a massive increase in viral replication compared to the precursor cells. Despite the low levels of Zika in the precursor cells, we noticed thousands of genes changing their expression, showcasing how sensitive these cells are to Zika.

Assessing the genes affected, we discovered that Zika infection leads to a lot of changes connected to cell growth, communication, and even a type of cell death that helps trigger an immune response. This suggests Zika may help the body clear out tumor cells.

#What Happens Post-Infection

The response to Zika infection also highlighted different biological processes in the tumor cells. We saw a strong reaction in pathways related to inflammation and immune response as the tumor cells reacted to the virus.

By the 24-hour mark, we noticed key terms related to cell interaction and survival were downregulated. This implies that while Zika was creating chaos, it was also pushing the tumor cells toward their demise.

#The Role of TNF-alpha

Another important aspect of our findings was regarding TNF-alpha, a key protein involved in Immune Responses. After Zika infection, both types of tumor cells showed a significant increase in TNF-alpha.

When we investigated the clinical significance of this increase, we found that higher TNF-alpha levels were often linked to worse survival in patients with medulloblastoma. But there’s a twist; even though TNF-alpha usually promotes tumor growth, it may also help enhance the effectiveness of Zika therapy by making the tumor cells more likely to die when infected with the virus.

#The Secretome and How It Can Help

Delving deeper, we looked into the proteins released by Zika-infected tumor cells – their secretome. We found a wide range of Cytokines, which are important for communication between cells, particularly in immune responses. The changes in secretions showed that Zika can lead to pro-inflammatory signals, which might help the immune system better attack the tumors.

Interestingly, many of these secreted proteins are already used in therapies, meaning that Zika infection might boost results when combined with existing treatments.

#Targeting the Tumor Microenvironment

We also took a closer look at the tumor microenvironment (TME) – the area surrounding the tumor, where various cells interact and influence tumor growth. Our analysis indicated that the pro-inflammatory cytokines released by Zika-infected tumor cells could lead to favorable changes in the TME.

Our findings suggest that the secreted proteins from Zika-infected cells may encourage immune cells to move into the TME, creating a more favorable environment for combating tumors.

#Modeling the Immune Response

To further understand how Zika-induced proteins could impact the immune system, we modeled how they might affect various immune cells. What we found was that many immune cells – particularly those involved in anti-tumor responses – were indeed primed to react to these signals.

These immune cells are like little soldiers waiting for the right command to attack the enemy (in this case, tumor cells). By analyzing this, we identified distinct activation states for multiple types of immune cells, indicating a potential tailored response following Zika infection.

#Conclusion

In summary, our study highlights the fascinating interaction between the Zika virus and pediatric brain tumors. We see potential in using Zika as a treatment method due to its ability to not only fight tumor cells directly but also stimulate a robust immune response.

While we've uncovered promising data about Zika's role, more research is needed to fully understand how we can leverage these insights in clinical settings. With the growing body of evidence showing Zika's therapeutic potential, we might be on the brink of something truly beneficial for treating aggressive childhood brain tumors.

In this battle against pediatric cancers, Zika might just be a not-so-secret weapon waiting to be used. So yes, let's keep our research hats on and our sense of humor intact, because the fight against cancer is one wild ride!