期刊
CANCER CELL
卷 39, 期 10, 页码 1361-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2021.08.005
关键词
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资金
- New York State Department of Health, NY, USA [DOH01-C31850GG-3450000]
- Katie Oppo Research Fund
- Swim Across America funds
- NCI [5P01CA013106]
- Ovarian Cancer Action [OCARC18-22]
- CSHL Cancer Center [P30-CA045508]
- NYU Perlmutter Cancer Center [P30CA016087]
The combination of MPLA and IFNγ can polarize tumor-associated macrophages to kill cancer cells, reducing primary tumor growth and metastasis. This approach also enhances chemotherapy response and suppresses metastasis, with both macrophages and T cells playing critical roles in the anti-metastatic effects. Engaging a systemic anti-tumor immune response through activation of macrophages and T cells may represent a promising strategy for cancer treatment.
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) gamma. MPLA + IFN gamma 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 + IFN gamma 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 (TNF alpha). MPLA and IFN gamma are used individually in clinical practice and together represent a previously unexplored approach for engaging a systemic anti-tumor immune response.
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