TH-MYCN tumors, but not tumor-derived cell lines, are adrenergic lineage, GD2+, and responsive to anti-GD2 antibody therapy

Abstract

Neuroblastoma is a commonly lethal solid tumor of childhood and intensive chemoradiotherapy treatment cures ~50% of children with high-risk disease. The addition of immunotherapy using dinutuximab, a monoclonal antibody directed against the GD2 disialoganglioside expressed on neuroblasts, improves survival when incorporated into front-line therapy and shows robust activity in regressing relapsed disease when combined with chemotherapy. Still, many children succumb to neuroblastoma progression despite receiving dinutuximab-based immunotherapy, and efforts to counteract the immune suppressive signals responsible are warranted. Animal models of human cancers provide useful platforms to study immunotherapies. TH-MYCN transgenic mice are immunocompetent and develop neuroblastomas at autochthonous sites due to enforced MYCN expression in developing neural crest tissues. However, GD2-directed immunotherapy in this model has been underutilized due to the prevailing notion that TH-MYCN neuroblasts express insufficient GD2 to be targeted. We demonstrate that neuroblasts in TH-MYCN -driven tumors express GD2 at levels comparable to human neuroblastomas but rapidly lose GD2 expression when explanted ex vivo to establish tumor cell lines. This occurs in association with a transition from an adrenergic to mesenchymal differentiation state. Importantly, not only is GD2 expression retained on tumors in situ, treatment with a murine anti-GD2 antibody, 14G2a, markedly extends survival in such mice, including durable complete responses. Tumors in 14G2a-treated mice have fewer macrophage and myeloid-derived suppressor cells in their tumor microenvironment. Our findings support the utility of this model to inform immunotherapy approaches for neuroblastoma and potential opportunities to investigate drivers of adrenergic to mesenchymal fate decisions.

RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity

“…While many reasons could account for the response failure of anti-GD2 immunotherapy for a fraction of patients, one of the hypotheses is that lineage switching may lead to low abundance of GD2 expression due to downregulation of GD2 synthase genes. A recent study has shown that cell lines derived from TH-MYCN transgenic tumors lost GD2 expression, accompanied with switching of cell state from ADRN to MES 76 . Another study further supported that neuroblastoma state transition to MES confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1 77 .…”

Conditional c-MYC activation in catecholaminergic cells drives distinct neuroendocrine tumors: neuroblastoma vs somatostatinoma

“…Recent advances in developing GD2-based CAR T and CAR NKT therapies have provided additional evidence showing the potential of anti-GD2 immunotherapy for patients with relapsed disease 41,44 . The Th-MYCN mouse model in the 129X1/SvJ background was responsive to anti-GD2 immunotherapy 81 . Here we focused on the Dbh-iCre;CAG-MYC syngeneic models and tested their responses to immunotherapies and targeted therapies.…”

Vitronectin-based hydrogels recapitulate neuroblastoma growth conditions

“…If higher VN integrated density is confirmed in VN/PEG hydrogels, the experiments should assess whether it is due to the presence of both synthesized and PEGylated VN (cells may preferentially grow on PEGylated VN spots or pericellularly reorganize PEGylated VN), or because an increased cell VN synthesis driven by PEGylated VN. Despite no statistical differences, the fact that VN expression is retained in vitro conditions indicates that VN/PEG hydrogels are susceptible for translational combinatory therapy studies as occurs with GD2 ( KO et al, 2022 ).…”