Sun et al. demonstrated that combination therapy with IFNγ and MPLA, a TLR4 agonist, inhibited tumor growth and metastasis in mouse models of breast and ovarian cancer. Weight and liver function were not impacted. In vitro, this combination induced iNOS-dependent tumoricidal activity in macrophages isolated from both mouse and human pleural effusion tumors. Protein and RNAseq analysis of mouse tumors harvested post-combination therapy showed increases in many chemokines and effector T cell response mediators. Markers of immunosuppression were reduced. Cisplatin enhanced the survival benefit observed with combination therapy.
Contributed by Margot O’Toole
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-2 (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.
Author Info: (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 Broo
Author Info: (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.
