Activating a collaborative innate-adaptive immune response to control breast and ovarian cancer metastasis

Sun, Lijuan, Kees, Tim, Almeida, Ana Santos, Liu, Bodu, He, Xue-Yan, Ng, David, Spector, David, McNeish, Iain A, Gimotty, Phyllis, Adams, Sylvia, Egeblad, Mikala (July 2020) Activating a collaborative innate-adaptive immune response to control breast and ovarian cancer metastasis. BioRxiv. (Unpublished)

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Abstract

Many cancers recruit monocytes/macrophages and polarize them into tumor-associated macrophages (TAMs). TAMs promote tumor growth and metastasis and inhibit cytotoxic T cells. Yet, macrophages can also kill cancer cells after polarization by e.g., lipopolysaccharide (LPS, a bacteria-derived toll-like receptor 4 [TLR4] agonist) and interferon gamma (IFNγ). They do so via nitric oxide (NO), generated by inducible NO synthase (iNOS). Altering the polarization of macrophages could therefore be a strategy for controlling cancer. Here, we show that monophosphoryl lipid A (MPLA, a derivative of LPS) with IFNγ activated macrophages isolated from metastatic pleural effusions of breast cancer patients to kill the corresponding patients’ cancer cells in vitro. Importantly, intratumoral injection of MPLA with IFNγ not only controlled local tumor growth but also reduced metastasis in mouse models of luminal and triple negative breast cancers. Furthermore, intraperitoneal administration of MPLA with IFNγ reprogrammed peritoneal macrophages, suppressed metastasis, and enhanced the response to chemotherapy in the ID8-p53−/− ovarian carcinoma mouse model. The combined MPLA+IFNγ treatment reprogrammed the immunosuppressive microenvironment to be immunostimulatory by recruiting leukocytes, stimulating type I interferon signaling, decreasing tumor-associated (CD206+) macrophages, increasing tumoricidal (iNOS+) macrophages, and activating cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor α (TNFα). Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFNγ. MPLA and IFNγ are already used individually in clinical practice, so our strategy to engage the anti-tumor immune response, which requires no knowledge of unique tumor antigens, may be ready for near-future clinical testing.

Item Type:	Paper
Subjects:	diseases & disorders > cancer > cancer types > breast cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell diseases & disorders > cancer > metastasis diseases & disorders > cancer > cancer types > ovarian cancer
CSHL Authors:	Kees, Tim Liu, Bodu He, Xueyan Ng, David Spector, David L. Egeblad, Mikala Sun, Lijuan Santos De Almeida, Ana Margarida
Communities:	CSHL labs > Egeblad lab CSHL labs > Spector lab CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	14 July 2020
Date Deposited:	13 Jul 2021 20:30
Last Modified:	13 Jul 2021 20:30
URI:	https://repository.cshl.edu/id/eprint/40286

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