Msp/ron signaling in tumor immunology: a novel candidate forpotentiating clinical responses to breast cancerimmunotherapy
Başlık çevirisi mevcut değil.
- Tez No: 716944
- Danışmanlar: DR. ALANA WELM
- Tez Türü: Doktora
- Konular: Onkoloji, Oncology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2018
- Dil: İngilizce
- Üniversite: University of Utah
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 256
Özet
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Özet (Çeviri)
Breast cancer is the most common form of aggressive cancer in women with more than 250,000 estimated new cases in the United States in 2017. Particularly, disseminated breast cancer remains a clinical challenge and will result in more than 40,000 deaths in 2017. Events governing the metastasis of breast cancer are incompletely understood; however, mounting evidence suggests the critical involvement of the immune system, especially during the outgrowth of seeded micrometastases. Utilization of anti-checkpoint therapeutics that take the brakes off of the immune system was shown to be effective in treating various cancers. Although complete responses are attainable with immunotherapy, only a fraction of the patients benefit from the treatment indicating the critical need for improvement. An increased understanding of the accessory immunosuppressive pathways is crucial to devise effective immunotherapies. RON is a receptor tyrosine kinase expressed on macrophages, epithelial cells and tumors. Overexpression of RON is a poor prognostic factor in breast cancer patients. Activation of RON promotes an immunosuppressive phenotype in macrophages and increases proliferation and migration of tumor cells. Tumor-intrinsic and -extrinsic effects of RON signaling are emerging as a critical factor for tumor progression and the suppression of anti-tumor immune responses. By utilizing an established mouse breast cancer model, we investigated the role of host RON signaling in regulating anti-tumor immunity and whether inhibition of RON can potentiate clinical responses to checkpoint immunotherapy. We found that host RON v signaling suppressed CD8+ T-cells allowing metastatic growth of breast cancer cells in the lungs. RON's activation in macrophages resulted in the upregulation of immune checkpoint ligands CD80 and PD-L1. Pharmacological inhibition or genetic loss of RON in combination with anti-CTLA-4, but not with anti-PD-1 immunotherapy, resulted in T-cell activation and reduced the tumor burden in both orthotopic and metastatic tumor settings, resulting in complete tumor clearance in a high proportion of mice. In summary, this dissertation sheds light on the molecular events ensuing RON's activation in macrophages and reveals a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer. Our findings will inform future development of RON inhibitors and breast cancer immunotherapy trials involving checkpoint therapeutics
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