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

Abstract

Heme oxygenase (HO)21 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.

Up‐regulation of PYK2/PKCα‐dependent haem oxygenase‐1 by CO‐releasing molecule‐2 attenuates TNF‐α‐induced lung inflammation

“…Mice were divided into seven groups, five mice in each group per cage and kept in standard individually ventilated cages in an animal facility under standardized conditions (12 h light/dark cycle, 21–24°C, humidity of 50–60%) with food and water ad libitum . For the in vivo treatment, zinc protoporphyrin IX (ZnPPIX) (Fest et al, ) and CORM‐2 were dissolved in DMSO at a concentration of 10 and 50 mg·mL −1 , respectively, and further diluted in PBS before injection. The final dosages for ZnPPIX and CORM‐2 were 1.64 and 8 mg·kg −1 (i.p.)…”

HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation

“…In addition, T regs recruitment is increased in HO-1-dependent manner in 4T1 breast cancer and in tumor-bearing mice [146] and HO-1 expression in cancer cells is related to the increased generation of IL-10 responsible for keeping DC immaturity [147,148]. …”

“…Moreover, in neuroblastoma samples, the univariate Kaplan–Meier analysis revealed that high HO-1 RNA expression levels are associated with an unfavorable prognosis [147] and, in histological samples of human glioma, HO-1 expression was higher in comparison to non-malignant brain tissue [187] with no differences among the various tumor grades. However, HO-1 protein expression was associated with a worse prognosis of grade II and III astrocytoma patients [187].…”

Overexpression of heme oxygenase-1 in bone marrow stromal cells promotes microenvironment-mediated imatinib resistance in chronic myeloid leukemia

“…The expression of HO-1 increases the production of CO, iron and biliverdin, enhances cell protection, resists apoptosis, promotes cell proliferation, reduces inflammatory response and so on [13]. High HO-1 expression can induce the resistance of tumor cells such as neuroblastoma [14,15]. Our group has also published a series of articles about the relationship between HO-1 and leukemia in recent years [16][17][18].…”