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Isolation of Group 2 Innate Lymphoid Cells from Mouse Nasal Mucosa to Detect the Expression of CD226
Published on: May 10, 2022
ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung
Martijn J Schuijs1, Shaun Png1, Arianne C Richard1,2
1CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
Abstract:
Metastasis constitutes the primary cause of cancer-related deaths, with the lung being a commonly affected organ. We found that activation of lung-resident group 2 innate lymphoid cells (ILC2s) orchestrated suppression of natural killer (NK) cell-mediated innate antitumor immunity, leading to increased lung metastases and mortality. Using multiple models of lung metastasis, we show that interleukin (IL)-33-dependent ILC2 activation in the lung is involved centrally in promoting tumor burden. ILC2-driven innate type 2 inflammation is accompanied by profound local suppression of interferon-γ production and cytotoxic function of lung NK cells. ILC2-dependent suppression of NK cells is elaborated via an innate regulatory mechanism, which is reliant on IL-5-induced lung eosinophilia, ultimately limiting the metabolic fitness of NK cells. Therapeutic targeting of IL-33 or IL-5 reversed NK cell suppression and alleviated cancer burden. Thus, we reveal an important function of IL-33 and ILC2s in promoting tumor metastasis via their capacity to suppress innate type 1 immunity.
Insights
Activation of lung group 2 innate lymphoid cells (ILC2s) suppresses natural killer (NK) cell antitumor immunity, increasing lung metastasis. Targeting IL-33 or IL-5 reversed this suppression, reducing cancer burden.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Metastasis is a leading cause of cancer mortality, often affecting the lungs.
- Innate immunity plays a critical role in controlling cancer progression and metastasis.
Purpose of the Study:
- To investigate the role of lung-resident group 2 innate lymphoid cells (ILC2s) in regulating natural killer (NK) cell-mediated antitumor immunity during lung metastasis.
- To elucidate the mechanisms by which ILC2s influence NK cell function and tumor burden.
Main Methods:
- Utilized multiple models of lung metastasis.
- Investigated the involvement of interleukin-33 (IL-33) and interleukin-5 (IL-5) signaling pathways.
- Assessed NK cell function, including interferon-γ production and cytotoxic activity.
- Analyzed the impact of eosinophilia on NK cell metabolic fitness.
Main Results:
- Activation of lung ILC2s suppressed NK cell-mediated innate antitumor immunity.
- ILC2s promoted lung tumor burden and mortality through IL-33-dependent mechanisms.
- ILC2s induced type 2 inflammation, suppressing NK cell cytotoxic function via IL-5-driven eosinophilia.
- Therapeutic targeting of IL-33 or IL-5 reversed NK cell suppression and reduced cancer burden.
Conclusions:
- ILC2s play a critical role in promoting tumor metastasis by suppressing innate type 1 immunity, specifically NK cell function.
- IL-33 and IL-5 signaling pathways are central to ILC2-mediated suppression of antitumor immunity.
- Targeting IL-33 or IL-5 presents a potential therapeutic strategy for reducing lung metastasis.
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