Targeting CXCR2+ PMN-MDSCs for immunotherapy of hepatoblastoma

Abstract Hepatoblastoma (HB) is the most common primary liver cancer of childhood. Although it has a 1.5/106 incidence, it is deadly in 20% of children, with a median age of diagnosis of 18 months. The treatment of HB with cytotoxic chemotherapy can lead to devastating side effects, and the role of immunotherapy in HB treatment has not been established. In our preliminary work, we discovered that neutrophilic myeloid-derived suppressor cells (PMN- MDSCs) are one of the most frequent components of the immune microenvironment of a well-characterized HB mouse model driven by the hydrodynamic delivery of YAP and activated β-catenin. When we systemically depleted PMN-MDSCs in the HB model, we found smaller tumors and an elevated level of CD8+ T cell frequency, proliferation, and activation. Together with the work of others establishing PMN-MDSCs as a major immunosuppressive cell type in non-HB primary liver tumors, we now propose an in-depth study to examine PMN-MDSCs as a potentially therapeutic target in HB. We hypothesize that HB-specific oncogenes lead to the recruitment of PMN-MDSCs, and that targeting PMN-MDSCs will sensitize HB tumors to ICI therapy. We will test the hypotheses in 2 Aims. In Aim 1, we will determine which oncogene drives PMN-MDSC recruitment by employing novel DNA constructs that allow for the doxycycline-inducible selective deletion of either YAP or β- catenin in the HB tumors of immunocompetent mice. In Aim 2, we will test an experimental CXCR2i (SB225002) in preclinical HB model and determine the effect on tumor growth. In addition, we will combine antibody-based depletion of PMN-MDSCs or CXCR2i with approved immune checkpoint inhibitors (ICIs) agents in order to test the potential of combination immunotherapy in HB. Altogether, this application combines innovative mouse genetic approaches with preclinical therapeutic studies to explore the regulation and targeting of MDSCs in HB pathogenesis. The research is highly innovative, mechanistic, and translational, and its results will aid in developing MDSC-targeting based therapeutics for HB treatment.