Neuroblastoma Formation Requires Unconventional CD4 T Cells and Arginase-1-Dependent Myeloid Cells

Cancer Res. 2021 Oct 1;81(19):5047-5059. doi: 10.1158/0008-5472.CAN-21-0691. Epub 2021 Jul 23.


Immune cells regulate tumor growth by mirroring their function as tissue repair organizers in normal tissues. To understand the different facets of immune-tumor collaboration through genetics, spatial transcriptomics, and immunologic manipulation with noninvasive, longitudinal imaging, we generated a penetrant double oncogene-driven autochthonous model of neuroblastoma. Spatial transcriptomic analysis showed that CD4+ and myeloid populations colocalized within the tumor parenchyma, while CD8+ T cells and B cells were peripherally dispersed. Depletion of CD4+ T cells or CCR2+ macrophages, but not B cells, CD8+ T cells, or natural killer (NK) cells, prevented tumor formation. Tumor CD4+ T cells displayed unconventional phenotypes and were clonotypically diverse and antigen independent. Within the myeloid fraction, tumor growth required myeloid cells expressing arginase-1. Overall, these results demonstrate how arginine-metabolizing myeloid cells conspire with pathogenic CD4+ T cells to create permissive conditions for tumor formation, suggesting that these protumorigenic pathways could be disabled by targeting myeloid arginine metabolism. SIGNIFICANCE: A new model of human neuroblastoma provides ways to track tumor formation and expansion in living animals, allowing identification of CD4+ T-cell and macrophage functions required for oncogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / genetics*
  • Arginase / metabolism
  • Biomarkers
  • Bone Marrow Cells / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Line, Tumor
  • Computational Biology / methods
  • Disease Models, Animal
  • Disease Susceptibility*
  • Gene Expression Profiling
  • Humans
  • Mice
  • Mice, Transgenic
  • Myeloid Cells / metabolism*
  • Neuroblastoma / etiology*
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Oncogenes
  • Single-Cell Analysis
  • Transcriptome


  • Biomarkers
  • ARG1 protein, human
  • Arginase