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.

Grant Number: 1R21CA292251-01A1
NIH Institute/Center: NIH
Principal Investigator: Xin Chen