MS2 Kirk Kerkorian School of Medicine Las Vegas, NV, US
Introduction: Immunotherapies for treating malignant childhood cancers have become increasingly popular due to their potential efficacy and favorable side effect profiles. Anti-CD47 monoclonal antibody therapy promotes specific phagocytosis of group 3 medulloblastoma cells by macrophages. Despite known age-dependent functional differences in macrophages, all previous anti-CD47 studies, including those of group 3 medulloblastoma, used adult macrophages and the implantation of tumors into adult mice to assess the efficacy of this treatment.
Methods: Here, we investigate whether the donor's age affects macrophages' ability to phagocytize group 3 medulloblastoma cells in vitro in response to anti-CD47 treatment. We conducted this study using three different medulloblastoma lines and macrophages from the human umbilical cord and adult peripheral blood sources.
Results: Anti-CD47 monoclonal antibody led to enhanced macrophage phagocytosis of tumor cells regardless of age. However, human umbilical cord blood-derived macrophages (UCDMs) phagocytosed tumor cells significantly more than adult peripheral blood-derived macrophages (APDMs) in response to anti-CD47. This result prompted us to investigate potential mechanisms by RNASeq and FACS. We found that APDMs expressed significantly more CD32b and LILRB4, potent negative regulators of antibody-dependent cell phagocytosis.
Conclusion : Our findings further prove the utility of targeting the CD47- SIRPa- axis in children with medulloblastoma. In addition to anti-CD47 immune checkpoint inhibitors, other immunomodulators should be considered for further upregulation of phagocytosis of tumor cells. Specifically, inhibition of LILRB4 and CD32b appears to have a potential role in enhancing tumor phagocytosis. We plan to investigate if lowering the expression of these negative phagocytosis regulators can further enhance the anti-tumor activities of adult and pediatric-derived macrophages.
.jpg)
