Etzerodt et al. show that specific depletion of the minor CD163+ (scavenger receptor) tumor-associated macrophage (TAM) subset mediated tumor regression in a mouse model of anti-PD-1-resistant metastatic melanoma. This effect was abrogated by deleting all TAMs or by inhibiting monocyte recruitment by deleting the CCR2 gene, but not by anti-PD-1 treatment. Specific CD163+ TAM depletion recruited and activated tumor-infiltrating, CCR2-dependent, bone marrow-derived monocytes and CD4+ and CD8+ T cells. CD163 expression is increased in pretreatment tumor biopsies from patients with BRAF/NRAS-driven metastatic melanoma refractory to anti-PD-1 therapy.
Contributed by Paula Hochman
Tumor-associated macrophages (TAMs) play critical roles in tumor progression but are also capable of contributing to antitumor immunity. Recent studies have revealed an unprecedented heterogeneity among TAMs in both human cancer and experimental models. Nevertheless, we still understand little about the contribution of different TAM subsets to tumor progression. Here, we demonstrate that CD163-expressing TAMs specifically maintain immune suppression in an experimental model of melanoma that is resistant to anti-PD-1 checkpoint therapy. Specific depletion of the CD163(+) macrophages results in a massive infiltration of activated T cells and tumor regression. Importantly, the infiltration of cytotoxic T cells was accompanied by the mobilization of inflammatory monocytes that significantly contributed to tumor regression. Thus, the specific targeting of CD163(+) TAMs reeducates the tumor immune microenvironment and promotes both myeloid and T cell-mediated antitumor immunity, illustrating the importance of selective targeting of tumor-associated myeloid cells in a therapeutic context.
Author Info: (1) Aix Marseille University, CNRS, INSERM, CIML, Marseille, France ae@biomed.au.dk. Department of Biomedicine, Aarhus University, Aarhus, Denmark. (2) Aix Marseille University, CN
Author Info: (1) Aix Marseille University, CNRS, INSERM, CIML, Marseille, France ae@biomed.au.dk. Department of Biomedicine, Aarhus University, Aarhus, Denmark. (2) Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. (3) Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark. Department of Dermatology, Yale University School of Medicine, New Haven, CT. (4) Department of Dermatology, Yale University School of Medicine, New Haven, CT. (5) Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. (6) Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. (7) Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, King's College London, London, UK. (8) Department of Dermatology, Yale University School of Medicine, New Haven, CT. (9) Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. (10) Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. (11) Department of Biomedicine, Aarhus University, Aarhus, Denmark. Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. (12) Aix Marseille University, CNRS, INSERM, CIML, Marseille, France toby.lawrence@kcl.ac.uk. Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, King's College London, London, UK. Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.
