157P - Therapeutic potential of B7-H3 targeting in pediatric neuroblastoma

Background

B7 immune checkpoint proteins are important regulators of antitumor immune response, and they can also mediate oncogenic signaling and cancer development. B7-family proteins and their receptors constitute prognostic, predictive and therapeutic relevant proteins in cancer immunotherapies.

Methods

We have performed analyses of B7-family members mRNA and protein expression in neuroblastoma tumors, in association with clinical-pathological parameters. We performed ectopic overexpression, silencing and CRISPR/Cas knockout experiments to analyze the role of B7-H3 (CD276) in neuroblastoma cell signaling and viability, drug sensitivity, and gene expression profile by RNA sequencing.

Results

We observed high expression of B7-H3 in neuroblastoma tumor cells, which associated with worse clinical outcome, including metastatic progression, in our cohort of 60 pediatric neuroblastoma patients. The expression, localization, and function of B7-H3 has been evaluated in human neuroblastoma cell lines and in neuroblastoma tumor samples. Overexpression of B7-H3 in neuroblastoma cells increased STAT3 signaling and decreased cell sensitivity to chemotherapy. Downregulation of B7-H3 expression resulted in decreased neuroblastoma cell viability and specific gene expression reprogramming.

Conclusions

Our findings support the hypothesis that B7-H3 modulates tumorigenicity in neuroblastoma. We unveil the effects of B7-H3 expression in neuroblastoma cell proliferation, therapy response, and gene expression, and propose targeting of B7-H3 as a suitable immunotherapeutic approach to improve current anticancer therapies in neuroblastoma.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

Biobizkaia Health Research Institute.

Funding

BIO20/CI/004 from BIOEF (EITB Maratoia, Spain), CP20/00008 from Instituto de Salud Carlos III (Spain and European Union), Asociación NEN (Spain), and Fundación Gangoiti (Spain). ERI has received a predoctoral fellowship from Asociación Española Contra el Cáncer (AECC, Junta Provincial de Bizkaia, Spain, PRDVZ222375REY). ME has received a Biobizkaia Fellowship 2023/2024 (Spain).

Disclosure

All authors have declared no conflicts of interest.