{
  "abstract": "Background Macrophages are the most abundant immune cell population in the tumor microenvironment (TME) and are often associated with poor therapeutic outcome. However, clinical strategies aiming to deplete these cells or prevent their recruitment have failed. Importantly, macrophages are functionally diverse, including immuno-suppressive subsets and subsets that support T cell based immunotherapies. Macrophage targeting, therefore, requires specific targeting of suppressive populations. CD163 high macrophages are a macrophage subset that strongly suppresses spontaneous tumor immunity and impairs the response to therapeutic vaccination in mice.1 Here, we show that CD163high macrophages are an immunotherapeutic target, either standalone or in combination with immune checkpoint inhibition (ICI) or therapeutic vaccination.Methods Using doxorubicin-loaded nanoparticles targeted towards CD163, we depleted CD163 high macrophages in five different mouse tumor models, alone or in combination with ICI or therapeutic vaccination. The TME of treated mice was assessed with multispectral flow cytometry. CD163high macrophages’ transcriptomes was analyzed by bulk RNA-seq.Results In one model, CD163 depletion worked as an effective monotherapy, resulting in tumor regression and long-term antitumor memory responses. In this model, the tumor microenvironment of CD163-depleted tumors had less regulatory T cells (Tregs), more active CD8 + and CD4+ T cells and more iNOS+ CD86+ inflammatory macrophages. Depletion experiments revealed that tumor regression was dependent on CD8 T cells, but not on CD4 T cells. In other models, CD163 depletion sensitized tumors to ICI or therapeutic vaccination. Transcriptomic analyses revealed that CD163high macrophages had a strong anti-inflammatory ‘M2-like’ phenotype and the potential to utilize several immunosuppressive mechanisms. The exact suppressive mechanisms deployed differ per model and/or therapy analyzed, and may reflect different intratumoral distribution and macrophage heterogeneity. For instance, immunosuppression was mediated via heme oxygenase-1 (HO-1) signaling in only one model. In patients, CD163high macrophages form a heterogenous population of cells that are present in a series of different tumors. However, the most abundant subgroup is associated with resistance to immune checkpoint therapy and has a transcriptome similar to that of murine CD163high tumor macrophages, indicating that CD163high macrophages likely have similar immunosuppressive functions in mouse and human.Conclusions Collectively, this data shows that although CD163 high macrophages’ immunosuppressive mechanisms vary between models, they are a robust immunosuppressive population that show promise as an immunotherapeutic target. Current work focuses on understanding the heterogeneous immunosuppressive mechanisms of CD163high macrophages and in vivo targeting using antibody-drug conjugates.",
  "authors": [
    {
      "affiliations": [
        "Leiden University Medical Center, Oncode Institute, Leiden, Netherlands"
      ],
      "name": "Pieter Schol"
    },
    {
      "affiliations": [
        "Leiden University Medical Center, Oncode Institute, Leiden, Netherlands"
      ],
      "name": "Maarten Nijen Twilhaar"
    },
    {
      "affiliations": [
        "Leiden University Medical Center, Oncode Institute, Leiden, Netherlands"
      ],
      "name": "Camilla Labrie"
    },
    {
      "affiliations": [
        "Leiden University Medical Center, Oncode Institute, Leiden, Netherlands"
      ],
      "name": "Roderick Slieker"
    },
    {
      "affiliations": [
        "University of Southern Denmark, Odense, Denmark"
      ],
      "name": "Jonas Graversen"
    },
    {
      "affiliations": [
        "Aarhus University, Aarhus, Denmark"
      ],
      "name": "Anders Etzerodt"
    },
    {
      "affiliations": [
        "Leiden University Medical Center, Oncode Institute, Leiden, Netherlands"
      ],
      "name": "Tetje van der Sluis"
    },
    {
      "affiliations": [
        "Leiden University Medical Center, Oncode Institute, Leiden, Netherlands"
      ],
      "name": "Sjoerd H van der Burg"
    }
  ],
  "title": "794 CD163+ macrophages are an effective target for antitumor therapy",
  "uid": "169a6d14-b99c-557f-a1cd-a38855b9cc3b"
}