1. Academic Validation
  2. 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.
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.

Figures
Products