Activating a collaborative innate-adaptive immune response to control metastasis

  • Cancer Cell. 2021 Oct 11;39(10):1361-1374.e9. doi: 10.1016/j.ccell.2021.08.005.
Lijuan Sun  1 ,  Tim Kees  1 ,  Ana Santos Almeida  1 ,  Bodu Liu  1 ,  Xue-Yan He  1 ,  David Ng  1 ,  Xiao Han  2 ,  David L Spector  1 ,  Iain A McNeish  3 ,  Phyllis Gimotty  4 ,  Sylvia Adams  5 ,  Mikala Egeblad  6
Affiliations
  • 1. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • 2. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Graduate Program in Genetics, Stony Brook University, Stony Brook, NY 11794, USA.
  • 3. Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
  • 4. Department of Biostatistics, Epidemiology & Informatics, University of Pennsylvania, Philadelphia, PA 19104-6021, USA.
  • 5. Perlmutter Cancer Center, New York University, New York, NY 10016, USA.
  • 6. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: [email protected].
PMID: 34478639 DOI: 10.1016/j.ccell.2021.08.005
Abstract

Tumor-associated macrophages (TAMs) promote metastasis and inhibit T cells, but macrophages can be polarized to kill Cancer cells. Macrophage polarization could thus be a strategy for controlling Cancer. We show that macrophages from metastatic pleural effusions of breast Cancer patients can be polarized to kill Cancer cells with monophosphoryl lipid A (MPLA) and interferon (IFN) γ. MPLA + IFNγ injected intratumorally or intraperitoneally reduces primary tumor growth and metastasis in breast Cancer mouse models, suppresses metastasis, and enhances chemotherapy response in an ovarian Cancer model. Both macrophages and T cells are critical for the treatment's anti-metastatic effects. MPLA + IFNγ stimulates type I IFN signaling, reprograms CD206+ TAMs to inducible NO Synthase (iNOS)+ macrophages, and activates cytotoxic T cells through macrophage-secreted interleukin-12 (IL-12) and tumor necrosis factor alpha (TNFα). MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach for engaging a systemic anti-tumor immune response.

Keywords
IFNγ; MPLA; anti-tumor immune response; breast cancer; cytotoxic T cells; metastasis treatment; ovarian cancer; tumor-associated macrophages.
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