Targeting a scavenger receptor on tumor-associated macrophages activates tumor cell killing by natural killer cells

Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):32005-32016. doi: 10.1073/pnas.2015343117. Epub 2020 Nov 23.


Tumor-associated macrophages (TAMs) can have protumor properties, including suppressing immune responses, promoting vascularization and, consequently, augmenting tumor progression. To stop TAM-mediated immunosuppression, we use a novel treatment by injecting antibodies specific for scavenger receptor MARCO, which is expressed on a specific subpopulation of TAMs in the tumor. We now report the location of this TAM as well as the pleiotropic mechanism of action of anti-MARCO antibody treatment on tumor progression and further show that this is potentially relevant to humans. Using specific targeting, we observed decreased tumor vascularization, a switch in the metabolic program of MARCO-expressing macrophages, and activation of natural killer (NK) cell killing through TNF-related apoptosis-inducing ligand (TRAIL). This latter activity reverses the effect of melanoma cell-conditioned macrophages in blocking NK activation and synergizes with T cell-directed immunotherapy, such as antibodies to PD-1 or PD-L1, to enhance tumor killing. Our study thus reveals an approach to targeting the immunosuppressive tumor microenvironment with monoclonal antibodies to enhance NK cell activation and NK cell-mediated killing. This can complement existing T cell-directed immunotherapy, providing a promising approach to combinatorial immunotherapy for cancer.

Keywords: immunotherapy; melanoma; tumor associated macrophages.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Male
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Melanoma / pathology
  • Mice
  • Mice, Knockout
  • Primary Cell Culture
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Tumor-Associated Macrophages / drug effects*
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism


  • Immune Checkpoint Inhibitors
  • MARCO protein, human
  • Marco protein, mouse
  • Receptors, Immunologic
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tnfsf10 protein, mouse