Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity

J Exp Med. 2018 Mar 5;215(3):877-893. doi: 10.1084/jem.20171435. Epub 2018 Feb 7.


Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state. Combination therapy reduced the frequency of these subsets, while simultaneously inducing a separate polyfunctional inflammatory TAM subset cosecreting TNF-α, IL-6, and IL-12. Tumor suppression by this combined therapy was partially dependent on T cells, and on TNF-α and IFN-γ. Together, this study demonstrates the potential for targeting TAMs to convert a "cold" into an "inflamed" tumor microenvironment capable of eliciting protective T cell responses.

Publication types

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

MeSH terms

  • Animals
  • CD40 Antigens / agonists
  • CD40 Antigens / metabolism
  • Cell Proliferation
  • Immunotherapy*
  • Inflammation / pathology*
  • Interferon-gamma / metabolism
  • Macrophages / metabolism
  • Macrophages / pathology
  • Melanoma, Experimental / pathology
  • Mice
  • Myeloid Cells / pathology*
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • PTEN Phosphohydrolase / metabolism
  • Phenotype
  • Proto-Oncogene Proteins B-raf / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Survival Analysis
  • T-Lymphocytes / immunology
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / metabolism


  • CD40 Antigens
  • RNA, Messenger
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Proto-Oncogene Proteins B-raf
  • PTEN Phosphohydrolase