Activating a collaborative innate-adaptive immune response to control metastasis

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. [Display omitted] •MPLA + IFNγ repolarizes TAMs from mice and patients to tumoricidal macrophages•MPLA + IFNγ activates cytotoxic T cells through macrophage-secreted IL-12 and TNFα•MPLA + IFNγ suppresses tumor growth and metastasis in breast and ovarian cancer models•MPLA + IFNγ enhances the response to chemotherapy in ovarian cancer Sun et al. combine monophosphoryl lipid A (MPLA) with interferon γ (IFNγ) to reprogram macrophages, activate cytotoxic T cells, suppress tumor growth and metastasis, and enhance chemotherapy response in mice. MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach for eliciting anti-metastatic responses.