Activation of NF-kB in Neuroblastoma Myeloid Cells

Johns Hopkins University School of Medicine, Baltimore, MD

Malignant tumors develop means to evade the immune system. An exciting recent advance is the use of checkpoint inhibitors to reactivate T cells within the immune system, which has led to major responses in several cancers. Myeloid cells are a second key component of the immune system. Cancers attract myeloid cells and stimulate them to adopt tumor-promoting M2 features. Conversion of tumor myeloid cells to the anti-cancer M1 state would represent a new immunotherapy strategy. Myeloid cells that lack a protein called NF-?B p50 adopt M1 features and cannot be directed to become M2 by cancers. Several cancers grow slower in mice lacking p50, and when we treat mice with myeloid cells lacking p50, several types of tumors respond. This proposal seeks to use mouse models to validate and optimize p50-deficient myeloid cell therapy against neuroblastoma, a pediatric cancer that is often highly aggressive in patients over 18 months of age. Aim 1 will determine whether neuroblastoma grows slower in mice lacking p50. Aim 2 will determine whether infusion of myeloid cells lacking p50 slows neuroblastoma tumor growth. In both aims, we will also evaluate whether combining T cell checkpoint inhibitors or agents that modify DNA to stimulate the immune response with myeloid cells lacking p50 benefits therapy of neuroblastoma. Successful completion of these studies will encourage us to test the utility of myeloid cells lacking NF-kB p50 as a novel immunotherapy for patients with neuroblastoma.