2. Academic Validation
  3. Activating a collaborative innate-adaptive immune response to control metastasis

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

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: egeblad@cshl.edu.
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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