Neuroblastoma Formation Requires Unconventional CD4 T Cells and Arginase-1-Dependent Myeloid Cells
- PMID: 34301764
- PMCID: PMC8488023
- DOI: 10.1158/0008-5472.CAN-21-0691
Neuroblastoma Formation Requires Unconventional CD4 T Cells and Arginase-1-Dependent Myeloid Cells
Abstract
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.
©2021 The Authors; Published by the American Association for Cancer Research.
Conflict of interest statement
P.G. Thomas reports grants from NIH-National Institute of Allergy and Infectious Diseases (NIAID), NIH-NCI, and Key For a Cure Foundation, and grants and other support from ALSAC during the conduct of the study; personal fees and nonfinancial support from 10X Genomics and Illumina, and personal fees from Immunoscape and PACT Pharma outside the submitted work; and a patent for WO US US20190040381A1 pending, a patent for WO WO2021003114A2 pending, a patent for WO WO2020257575A1 pending, and a patent for WO US US20170304293A1 issued. P.J. Murray reports other support from Max Planck Gesellschaft, American Lebanese Syrian Associated Charities, and grants from Key For A Cure Foundation, NIH, and Deutsche Forschungsgemeinschaft during the conduct of the study, and is on the scientific advisory boards for Palleon Pharma and ImCheck Therapeutics. No activities for these advisory boards are related to the manuscript. P.J. Murray also has a research contract with Boehringer Ingelheim (Biberach an der Ries, Germany) concerning inflammation research, which is unrelated to the manuscript. No disclosures were reported by the other authors.
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