ABSTRACT
Despite aggressive treatment, the 5-year event-free survival rate for children with high-risk neuroblastoma is <50%. While most high-risk neuroblastoma patients initially respond to treatment, often with complete clinical remission, many eventually relapse with therapy-resistant tumors. Novel therapeutic alternatives that prevent the recurrence of therapy-resistant tumors are urgently needed. To understand the adaptation of neuroblastoma under therapy, we analyzed the transcriptomic landscape in 46 clinical tumor samples collected before (PRE) or after (POST) treatment from 22 neuroblastoma patients. RNA sequencing revealed that many of the top-upregulated biological processes in POST MYCN amplified (MNA+) tumors compared to PRE MNA+ tumors were immune-related, and there was a significant increase in numerous genes associated with macrophages. The infiltration of macrophages was corroborated by immunohistochemistry and spatial digital protein profiling. Moreover, POST MNA+ tumor cells were more immunogenic compared to PRE MNA+ tumor cells. To find support for the macrophage-induced outgrowth of certain subpopulations of immunogenic tumor cells following treatment, we examined the genetic landscape in multiple clinical PRE and POST tumor samples from nine neuroblastoma patients revealing a significant correlation between an increased amount of copy number aberrations (CNA) and macrophage infiltration in POST MNA+ tumor samples. Using an in vivo neuroblastoma patient-derived xenograft (PDX) chemotherapy model, we further show that inhibition of macrophage recruitment with anti-CSF1R treatment prevents the regrowth of MNA+ tumors following chemotherapy. Taken together, our work supports a therapeutic strategy for fighting the relapse of MNA+ neuroblastoma by targeting the immune microenvironment.
Acknowledgments
Spatial digital protein profiling was performed in the SpatialOmics@LU core facility at Lund University.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Author contributions
CH and DG designed and supervised the research. All authors performed the research and discussed the results. AV, GC, and CH wrote the manuscript. All authors provided comments and feedback. All the authors have read and approved the final manuscript.
Data availability statement
Research data supporting this publication is available at DOI 10.17044/scilifelab.22188583.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2184130
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.