Targeting of heme oxygenase‐1 as a novel immune regulator of neuroblastoma

Heme oxygenase (HO)−1 catalyzes the degradation of cytotoxic heme into biliverdin and blocks antitumor immune responses, thus protecting cancer against host defense. Whether this scenario also applies to neuroblastoma (NB), the most common extracranial solid childhood tumor, is not known. Here, we demonstrate for the first time a prognostic relevance of HO‐1 expression in samples from NB patients and show that targeting of HO‐1 prevents both cancer resistance against cellular stress and immune escape in the syngeneic NXS2 A/J mouse model of NB. High HO‐1 RNA expression in NB tissues emerged as unfavorable prognostic marker, in particular for patients older than 18 months as indicated by univariate as well as multivariate survival probability analyses including disease stage and MYCN status. On the basis of this observation we aimed to target HO‐1 by systemic as well as tumor‐specific zinc protoporphyrin‐mediated HO‐1 suppression in a syngeneic immunocompetent NB mouse model. This resulted in 50% reduction of primary tumor growth and a suppression of spontaneous liver metastases. Importantly, HO‐1 inhibition abrogated immune cell paralysis affecting CD4 and CD8 T‐effector cells. This in turn reverted HO‐1‐dependent immune escape mechanisms in NB by increasing NB apoptosis and improved DC maturation. In summary, HO‐1 emerges as a novel immune regulator in NB and emerges as a promising target for the development of therapeutic approaches. What's new? Aggressive neuroblastoma is resistant to virtually every therapeutic agent available, owing to remarkable properties of cell protection and immune evasion. Likely enabling those properties is heme oxygenase 1 (HO‐1), which is significantly up‐regulated in chemoresistant neuroblastoma cell lines. This study shows that HO‐1 up‐regulation is an unfavorable prognostic marker in high‐risk neuroblastoma patients, especially among patients older than 18 months. In neuroblastoma mice, targeted suppression of HO‐1 significantly reduced tumor growth and liver metastasis. The findings highlight the prognostic and therapeutic relevance of HO‐1 in high‐risk neuroblastoma, potentially informing improvements in treatment regimens.