T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Ilaria Marigo, Serena Zilio, Giacomo Desantis, Bernhard Mlecnik, Andrielly H R Agnellini, Stefano Ugel, Maria Stella Sasso, Joseph E. Qualls, Franz Kratochvill, Paola Zanovello, Barbara Molon, Carola H. Ries, Valeria Runza, Sabine Hoves, Amélie M. Bilocq, Gabriela Bindea, Emilia M C Mazza, Silvio Bicciato, Jérôme Galon, Peter J. MurrayVincenzo Bronte

Research output: Contribution to journalArticle

Abstract

Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8+ cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1+ myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies.

Original languageEnglish
Pages (from-to)377-390
Number of pages14
JournalCancer Cell
Volume30
Issue number3
DOIs
Publication statusPublished - Sep 12 2016

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Marigo, I., Zilio, S., Desantis, G., Mlecnik, B., Agnellini, A. H. R., Ugel, S., Sasso, M. S., Qualls, J. E., Kratochvill, F., Zanovello, P., Molon, B., Ries, C. H., Runza, V., Hoves, S., Bilocq, A. M., Bindea, G., Mazza, E. M. C., Bicciato, S., Galon, J., ... Bronte, V. (2016). T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells. Cancer Cell, 30(3), 377-390. https://doi.org/10.1016/j.ccell.2016.08.004