Journal Article
. 2020 Nov; 117(50):32005-32016.
doi: 10.1073/pnas.2015343117.

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

Silke Eisinger 1 Dhifaf Sarhan 1 Vanessa F Boura 1 Itziar Ibarlucea-Benitez 2 Sofia Tyystjärvi 1 Ganna Oliynyk 1 Marie Arsenian-Henriksson 1 David Lane 1 Stina L Wikström 3 Rolf Kiessling 3 Tommaso Virgilio 4 Santiago F Gonzalez 4 Dagmara Kaczynska 5 Shigeaki Kanatani 5 Evangelia Daskalaki 5 Craig E Wheelock 5 Saikiran Sedimbi 1 Benedict J Chambers 1 Jeffrey V Ravetch 6 Mikael C I Karlsson 7 
Affiliations
  • PMID: 33229588
  •     58 References
  •     18 citations

Abstract

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.

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