Friday, January 27, 2023
1/27/2023
PROJECT SUMMARY/ABSTRACT The sparse landscape of targetable mutations in pediatric cancers in general and neuroblastoma (NB) in particular, together with the recent successes of the anti-GD2 antibody, dinutuximab (2), provides a compelling rationale for further development of immune-based treatment strategies against this devastating cancer. However, responses to adoptive immunotherapy and checkpoint blockade have met with limited success, partly due to an incomplete understanding of the mechanisms underlying immune responsiveness or resistance in this tumor marked by significant heterogeneity. We undertook an unbiased clustering analysis of transcriptional signatures derived from a large primary NB data set and identified a subset of tumors, characterized by the high expression of immune response activation and suppression genes, and indicating the potential for eliciting an anti-tumor immune response. These signatures were seen mainly in tumors of the mesenchymal (MES) lineage, one of the two epigenetically regulated cell states in NB, comprised of undifferentiated malignant cells with primitive neural crest-like properties. By contrast, tumors with committed, adrenergic (ADR) neuron-like malignant cells were less immunogenic and exhibited PRC2-mediated suppression of key tumor cell-intrinsic immune activation genes. These promising results led to our central hypothesis that cell lineage state is an important predictor of immune therapy response in NB. In Aim 1, we will elucidate the epigenetic mechanisms underlying lineage-specific activation of immune response genes. Aim 2 will assess lineage- dependent functions of cytotoxic T cells in tumor control by determining whether MES NB cells possess an inflamed TME that facilitates cell-based therapies. In Aim 3, we will determine whether the increased expression of NK cell receptor ligands in MES tumors translates into response to NK cell therapy and whether PRC2 inhibition will augment such responses in ADR tumors alone or in combination dinutuximab. Together, these studies are expected to provide a compelling rationale for the use of tumor cell lineage for the selection of patients who are most likely to benefit from immunotherapy and to pre-clinically validate treatment strategies involving combinations of epigenetic and immune-based therapies to target the specific immune evasion mechanisms deployed by NB cells, our long-term goal.
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