PRJNA662418
A novel model of pediatric neuroblastoma
We generated a penetrant autochthonous model of neuroblastoma to quantify tumor growth non-invasively. We validated this model with direct transcriptional and histological comparisons to pediatric neuroblastoma cases. Single-cell analysis of parenchymal immune populations identified multiple populations of monocytes and macrophages, along with CD8+ and CD4+ T cells, including a subset expressing Foxp3. The expression of the amino acid catabolizing enzymes Arg1, IDO1, IDO2, and IL4i1 was observed in macrophages and monocytes, and, for IL4i1, B cells. Tumor growth was dependent on myeloid-specific expression of arginase 1 (Arg1) or pathways of programmed myeloid tryptophan metabolism (IDO1, IDO2, IL4i1), whose expression patterns mirrored human neuroblastomas. Mechanistically, low amino acid environments that result from enzymatic activity, as found in tumors, induced CD4+ T cells to adopt a unique Foxp3+ regulatory phenotype that was modulated in response to nutrient levels. Spatial transcriptomic analysis identified tumor infiltration and co-localizaiton of CD4+ and myeloid populations, while CD8+ T cells and B cells were not well-dispersed in the tumor parenchyma. Overall, our results suggest that amino acid-metabolizing myeloid cells work in concert with pathogenic CD4+ T cells to create conditions that allow tumor formation. These findings establish an unappreciated potency of macrophage amino acid metabolism in promoting malignancy and suggest that these tumorigenic pathways can be disabled by targeting myeloid amino acid metabolism.