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

Cancer Cell. 2016 Sep 12;30(3):377-390. doi: 10.1016/j.ccell.2016.08.004.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arginase / biosynthesis
  • Arginase / immunology
  • CD40 Antigens / immunology
  • CD40 Ligand / immunology
  • Cell Line, Tumor
  • Dendritic Cells / immunology*
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / immunology*
  • Neoplasms / therapy*
  • Nitric Oxide Synthase Type II / biosynthesis
  • Nitric Oxide Synthase Type II / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Microenvironment
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / immunology*

Substances

  • CD40 Antigens
  • Tumor Necrosis Factor-alpha
  • CD40 Ligand
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • Arginase