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A Perspective on the CD47-SIRPA Axis in High-Risk Neuroblastoma
Xao X Tang1, Hiroyuki Shimada2, Naohiko Ikegaki1
1Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Insights
This study explores the role of SIRPA in high-risk neuroblastoma, suggesting targeting SIRPA on macrophages may be more effective than CD47 for immunotherapy. This approach could enhance anti-tumor responses in pediatric cancer.
Area of Science:
- Pediatric Oncology
- Cancer Immunotherapy
- Tumor Immunology
Background:
- Neuroblastoma is a heterogeneous pediatric cancer with poor outcomes for high-risk cases.
- Macrophages are key effector cells in high-risk neuroblastoma, and their function is modulated by immune checkpoints.
- The CD47-SIRPA axis, a "don't eat me" signal, plays a critical role in tumor immune evasion.
Purpose of the Study:
- To discuss the function of SIRPA (Signal Regulatory Protein Alpha) in regulating tumor-associated macrophages (TAMs) in high-risk neuroblastoma.
- To evaluate the therapeutic potential of targeting the CD47-SIRPA pathway for pediatric neuroblastoma immunotherapy.
- To propose a novel strategy for macrophage-based immunotherapy in neuroblastoma.
Main Methods:
- Review and analysis of existing data on CD47 and SIRPA expression and function in neuroblastoma.
- Discussion of proposed mechanisms of action for anti-CD47 and anti-SIRPA therapies.
- Inference of macrophage polarization shifts based on published studies.
Main Results:
- SIRPA is expressed on macrophages, while its ligand CD47 is on tumor and stroma cells in neuroblastoma.
- High SIRPA expression correlates with a better disease outcome in neuroblastoma patients.
- Current anti-CD47 therapies face challenges, suggesting SIRPA-targeted approaches may be more suitable.
Conclusions:
- Targeting SIRPA on macrophages offers a promising alternative to CD47 blockade for neuroblastoma immunotherapy.
- Anti-SIRPA therapy, particularly F(ab')2 fragments, may maintain M1 macrophage polarization and enhance anti-tumor immunity.
- Combining SIRPA-targeted therapy with other immune-activating antibodies could improve phagocytosis and therapeutic efficacy.
Abstract:
Neuroblastoma is a pediatric cancer with significant clinical heterogeneity. Despite extensive efforts, it is still difficult to cure children with high-risk neuroblastoma. Immunotherapy is a promising approach to treat children with this devastating disease. We have previously reported that macrophages are important effector cells in high-risk neuroblastoma. In this perspective article, we discuss the potential function of the macrophage inhibitory receptor SIRPA in the homeostasis of tumor-associated macrophages in high-risk neuroblastoma. The ligand of SIRPA is CD47, known as a "don't eat me" signal, which is highly expressed on cancer cells compared to normal cells. CD47 is expressed on both tumor and stroma cells, whereas SIRPA expression is restricted to macrophages in high-risk neuroblastoma tissues. Notably, high SIRPA expression is associated with better disease outcome. According to the current paradigm, the interaction between CD47 on tumor cells and SIRPA on macrophages leads to the inhibition of tumor phagocytosis. However, data from recent clinical trials have called into question the use of anti-CD47 antibodies for the treatment of adult and pediatric cancers. The restricted expression of SIRPA on macrophages in many tissues argues for targeting SIRPA on macrophages rather than CD47 in CD47/SIRPA blockade therapy. Based on the data available to date, we propose that disruption of the CD47-SIRPA interaction by anti-CD47 antibody would shift the macrophage polarization status from M1 to M2, which is inferred from the 1998 study by Timms et al. In contrast, the anti-SIRPA F(ab')2 lacking Fc binds to SIRPA on the macrophage, mimics the CD47-SIRPA interaction, and thus maintains M1 polarization. Anti-SIRPA F(ab')2 also prevents the binding of CD47 to SIRPA, thereby blocking the "don't eat me" signal. The addition of tumor-opsonizing and macrophage-activating antibodies is expected to enhance active tumor phagocytosis.
