Cancer Cell
Volume 30, Issue 3, 12 September 2016, Pages 377-390
Journal home page for Cancer Cell

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

https://doi.org/10.1016/j.ccell.2016.08.004Get rights and content
Under an Elsevier user license
open archive

Highlights

  • 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

Summary

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.

Cited by (0)

10

Present address: Venetian Institute of Molecular Medicine (VIMM), 35129 Padova, Italy

11

Lead Contact