Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cancer cell, 2016-09, Vol.30 (3), p.377-390

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •Effective anti-tumor CD8+ T cell therapy requires expansion of Tip-DCs•Tip-DC differentiation depends on the affinity between TCR and MHC-peptide complexes•CD40/CD40L axis is necessary for tumor rejection mediated by CD8+ T cells•Favoring Tip-DC function in tumor environment enhances ACT efficacy Marigo et al. show that nitric oxide produced by Tip-DCs, a subset of tumor-infiltrating myeloid cells, is important for tumor control by adoptive cell therapy (ACT). Tip-DCs require the CD40-CD40L pathway but not CSF-1R; CSF-1R blockade reduces immunosuppressive macrophages and improves tumor control by ACT.