Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer
| Autor: | Sejin Chung, Mukund Seshadri, Erik S. Knudsen, Vishnu Kumarasamy, Amanda Ruiz, Scott I. Abrams, Jin Wu, Stephanie L. Tzetzo, Shailender S. Chauhan, Paris Vail, Agnieszka K. Witkiewicz, Jared Sivinski, Jianmin Wang, Ram Nambiar |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Myeloid medicine.medical_treatment Antigen presentation Cell Culture Techniques 03 medical and health sciences Mice 0302 clinical medicine Immune system Interferon Pancreatic cancer Cell Line Tumor medicine Animals Humans Molecular Targeted Therapy Immune Checkpoint Inhibitors Mitogen-Activated Protein Kinase Kinases business.industry Gastroenterology Cyclin-Dependent Kinase 4 Immunotherapy Cell Cycle Checkpoints Cyclin-Dependent Kinase 6 Cell cycle medicine.disease Xenograft Model Antitumor Assays Pancreatic Neoplasms Disease Models Animal 030104 developmental biology medicine.anatomical_structure Cell culture 030220 oncology & carcinogenesis Cancer research business medicine.drug Carcinoma Pancreatic Ductal Signal Transduction |
| Zdroj: | Gut. 70(1) |
| ISSN: | 1468-3288 |
| Popis: | ObjectiveThis study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer.DesignPatient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models. Single-cell RNA sequencing and multispectral imaging were employed to delineate effects on the immunological milieu in the tumour microenvironment.ResultsWe found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumour progression. These effects were associated with stable cell-cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single-cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors.ConclusionsTogether, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumour and immune microenvironment. This combination-targeted treatment can promote robust tumour control in combination with immune checkpoint inhibitor therapy. |
| Databáze: | OpenAIRE |
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