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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models
Myriam Lamrani1, Nejia Sassi1, Catherine Paul1
1EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; Univ. Bourgogne Franche-Comté, LIIC EA7269, Dijon, France; INSERM U 866, Burgundy University, Dijon, France.
Abstract:
Toll-like receptor (TLR) 4 agonists have emerged as a new group of molecules used for cancer therapy. They have been exploited to enhance the immunogenicity of current chemotherapeutic regimens. However, their effects on cancer cells remain elusive. Here, we showed that a TLR4 agonist, namely a synthetic lipid A analog (ALA), OM-174, exhibits antitumor effects in several mammary tumor mouse models. We also showed that immune components are involved in such effects, as attested to by the failure of ALA to induce tumor regression or an increase of animal survival in mice knocked-out for interferon γ (IFNγ) or TLR4. TLR4 and IFNγ receptor (INFR2) expressed by cancer cells are involved in the antitumor efficacy of ALA since this last did not inhibit tumor growth in mice bearing a tumor but lacking TLR4 or IFNγ receptor 2 (IFNR2). Mechanistic investigations revealed that nitric oxide (NO), superoxide and peroxynitrite produced by uncoupling of inducible NO synthase (NOS II) in cancer cells are key mediators of ALA and IFNγ-mediated tumor growth inhibition. We present here a comprehensive picture of tumor cell death induction, in vivo and in vitro, by immunotherapy and for the first time the involvement of the TLR4/IFNγ/NOS II pathway in immunotherapy was investigated.
Insights
Toll-like receptor 4 agonists, like OM-174, show antitumor effects in mammary tumors. This immunotherapy relies on Toll-like receptor 4 and interferon gamma signaling in cancer cells.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Toll-like receptor (TLR) 4 agonists are explored for cancer therapy to boost immune responses.
- Their direct impact on cancer cells and the underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the antitumor effects of a synthetic lipid A analog (ALA), OM-174, a TLR4 agonist.
- To elucidate the roles of TLR4, interferon gamma (IFNγ), and nitric oxide synthase II (NOS II) in ALA-mediated tumor inhibition.
Main Methods:
- Utilized mouse models of mammary tumors, including knockout mice for TLR4 and IFNγ receptor 2 (IFNR2).
- Assessed tumor regression, animal survival, and expression of key molecules.
- Investigated the production of nitric oxide (NO), superoxide, and peroxynitrite.
Main Results:
- OM-174 demonstrated significant antitumor effects in mammary tumor models.
- Antitumor efficacy was dependent on TLR4 and IFNγ signaling, as evidenced by studies in knockout mice.
- Cancer cell-intrinsic TLR4 and IFNR2 were crucial for OM-174's efficacy.
- Nitric oxide, superoxide, and peroxynitrite, generated via NOS II in cancer cells, were identified as key mediators.
Conclusions:
- The synthetic lipid A analog OM-174 exhibits potent antitumor activity through a pathway involving cancer cell-intrinsic TLR4 and IFNγ signaling.
- The TLR4/IFNγ/NOS II pathway is a critical mechanism for immunotherapy-induced tumor cell death.
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