How Does Chemotherapy Affect the Neuroblastoma Tumor-Immune Cell Microenvironment?

By Lauren Ingeno

The Findings

Children’s Hospital of Philadelphia researchers created the first longitudinal cell atlas of neuroblastoma, showing how 12 patients’ tumor microenvironments evolved after chemotherapy. Using advanced single cell sequencing and spatial omics techniques, the researchers found that interactions between tumor and immune cells changed after treatment.

Tumor cells that were more metabolically active were linked to worse outcomes, while patients with tumors that developed neuron-like features experienced a better prognosis. The presence of mesenchymal cells increased after treatment, and a higher number of these cells were associated with a poorer response to chemotherapy. The researchers also found that macrophages, a type of immune cell, changed to support tumor growth, blood vessel formation, and suppress the body’s immune response. Finally, the team discovered a communication pathway (HB-EGF/ERBB4) between macrophages and cancer cells that activated signals and promoted tumor growth.

Why It Matters

High-risk neuroblastoma is a leading cause of pediatric cancer mortality. Despite treatment advancements, the five-year survival rate for children is less than 50%. One challenge in treating the disease is that neuroblastoma cells are highly heterogeneous, meaning a single tumor can contain many different cell types.

While advancements in single-cell transcription and epigenomic profiling have enhanced the scientific community’s understanding of neuroblastoma, chemotherapy’s role in rewiring the tumor-immune cell microenvironment to promote treatment resistance remains unclear. Insights from this study could help researchers understand why some treatments fail and lead to better therapies for high-risk neuroblastoma by targeting these newly discovered mechanisms.

Who Conducted the Study

Kai Tan, PhD, a Professor of Pediatrics who spearheads CHOP’s participation in the National Cancer Institute (NCI) Human Tumor Atlas Network (HTAN), led the study. Other CHOP authors included John Maris, MD, the Giulio D'Angio Chair in Neuroblastoma Research; Kathrin Bernt, MD, an Associate Professor of Pediatrics; Michael Hogarty, MD, a Professor and Associate Director of the Hematology/Oncology Fellowship; and study lead author Wenbao Yu, PhD, a Research Assistant Professor in the Division of Oncology, among others.

How They Did It

The researchers used advanced single cell sequencing and spatial omics techniques to analyze the transcriptional, epigenetic, and proteomic profiles of tumor samples from 22 pediatric patients with high-risk neuroblastoma before and after they received chemotherapy. Their multidimensional dataset can be accessed from the HTAN data portal. 

Quick Thoughts

“Our atlas provides a crucial foundation for developing novel treatments by mapping the complex interactions between malignant cells and surrounding cells that support tumor growth,” Dr. Tan said.

What’s Next

Next, the researchers plan to use the HTAN data portal and conduct further analysis of neuroblastoma tumors to shed light on the molecular mechanisms of therapeutic resistance.

“As researchers, we look to use these insights to tailor therapies to target unique characteristics of a patient’s tumor,” Dr. Tan said. “Overall, we are optimistic about the doors our research and techniques are opening.”

Where the Study was Published

The findings were published in Nature Genetics. The research was supported by the National Cancer Institute (NCI) Human Tumor Atlas Network grant. Read more in a related CHOP press release.