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The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
Magdalena Paolino1, Axel Choidas2, Stephanie Wallner3
1IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
Abstract:
Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.
Insights
Blocking the Cbl-b protein in natural killer (NK) cells helps them reject metastatic tumors. A new small molecule inhibitor targeting TAM kinases, and even warfarin, showed potential in reducing cancer spread by activating NK cells.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Tumour metastasis is the leading cause of cancer mortality.
- Targeting immune inhibitory pathways offers new therapeutic strategies.
- Natural killer (NK) cells play a crucial role in immune surveillance against cancer.
Purpose of the Study:
- To investigate the role of E3 ubiquitin ligase Cbl-b in regulating NK cell activity against metastasis.
- To identify therapeutic targets for enhancing NK cell-mediated anti-metastatic activity.
- To explore the therapeutic potential of small molecule inhibitors and existing drugs targeting the Cbl-b/TAM pathway.
Main Methods:
- Genetic deletion and targeted inactivation of Cbl-b in mice.
- Identification of TAM tyrosine kinase receptors (Tyro3, Axl, Mer) as Cbl-b ubiquitylation substrates.
- In vivo administration of a novel small molecule TAM kinase inhibitor.
- Assessment of anti-metastatic activity of NK cells in murine cancer models.
- Evaluation of warfarin's anti-metastatic effects in relation to the Cbl-b/TAM pathway.
Main Results:
- Genetic deletion or inactivation of Cbl-b licensed NK cells to reject metastatic tumors.
- TAM receptors were identified as direct ubiquitylation substrates of Cbl-b.
- A novel small molecule TAM kinase inhibitor enhanced NK cell anti-metastatic activity in vivo.
- Oral or intraperitoneal administration of the TAM inhibitor significantly reduced murine mammary cancer and melanoma metastases.
- Warfarin demonstrated anti-metastatic activity in mice, mediated by the Cbl-b/TAM pathway in NK cells.
Conclusions:
- The Cbl-b/TAM pathway in NK cells is a critical regulator of anti-metastatic immunity.
- Targeting this pathway with small molecule inhibitors or drugs like warfarin can enhance NK cell function.
- This research opens avenues for developing novel 'pill' therapies to harness the innate immune system against cancer metastasis.
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