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

¹ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden.
² Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065.
³ Department of Oncology and Pathology, Karolinska Institutet, 17165 Stockholm, Sweden.
⁴ Institute for Research in Biomedicine, CH6500 Bellinzona, Switzerland.
⁵ Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17165 Stockholm, Sweden.
⁶ Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065; ravetch@rockefeller.edu mikael.karlsson@ki.se.
⁷ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden; ravetch@rockefeller.edu mikael.karlsson@ki.se.

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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