Neuroblastoma formation requires unconventional CD4 T cells and myeloid amino acid metabolism

Van de Velde, L.-A.; Allen, E. K.; Crawford, J. C.; Wilson, T. L.; Guy, C. S.; Russier, M.; Zeitler, L.; Bahrami, A.; Finkelstein, D.; Pelletier, S.; Schultz-Cherry, S.; Thomas, P. G.; Murray, P. J.

doi:10.1101/2021.02.08.430292

bioRxiv · 10.1101/2021.02.08.430292

Neuroblastoma formation requires unconventional CD4 T cells and myeloid amino acid metabolism

Van de Velde, L.-A.·Allen, E. K.·Crawford, J. C.·Wilson, T. L.·Guy, C. S.·Russier, M.·Zeitler, L.·Bahrami, A.·Finkelstein, D.·Pelletier, S.·Schultz-Cherry, S.·Thomas, P. G.·Murray, P. J.

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Abstract

By mirroring their function as tissue repair organizers in normal tissues, immune cells regulate tumor growth. To understand the different facets of immune-tumor collaboration through genetics, spatial transcriptomics, and immunological manipulation with non-invasive, longitudinal imaging, we generated a penetrant double oncogene-driven autochthonous model of neuroblastoma. Using spatial transcriptomic analysis, we co-localized CD4+ and myeloid populations 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+, or NK cells, prevented tumor formation. Tumor CD4+ T cells displayed unconventional phenotypes, were clonotypically diverse, and antigen-independent. Within the myeloid fraction, tumor growth required myeloid cells expressing Arginase-1. Overall, our results suggest that arginine-metabolizing myeloid cells conspire with pathogenic CD4+ T cells to create permissive conditions for tumor formation, and therefore suggest that these pro-tumorigenic pathways can be disabled by targeting myeloid amino acid metabolism.

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Van de Velde, L.-A., Allen, E. K., Crawford, J. C., Wilson, T. L., Guy, C. S., Russier, M., Zeitler, L., Bahrami, A., Finkelstein, D., Pelletier, S., Schultz-Cherry, S., Thomas, P. G., Murray, P. J.. 2021-02-08. Neuroblastoma formation requires unconventional CD4 T cells and myeloid amino acid metabolism. https://doi.org/10.1101/2021.02.08.430292

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