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Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer.
Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer.
- Source :
-
Gut [Gut] 2021 Jan; Vol. 70 (1), pp. 127-138. Date of Electronic Publication: 2020 May 18. - Publication Year :
- 2021
-
Abstract
- Objective: This study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer.<br />Design: Patient-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.<br />Results: We 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.<br />Conclusions: Together, 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.<br />Competing Interests: Competing interests: None declared.<br /> (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
- Subjects :
- Animals
Cell Culture Techniques
Cell Cycle Checkpoints
Cell Line, Tumor
Cyclin-Dependent Kinase 4 antagonists & inhibitors
Cyclin-Dependent Kinase 6 antagonists & inhibitors
Disease Models, Animal
Humans
Mice
Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors
Signal Transduction
Xenograft Model Antitumor Assays
Carcinoma, Pancreatic Ductal therapy
Immune Checkpoint Inhibitors therapeutic use
Molecular Targeted Therapy
Pancreatic Neoplasms therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 70
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 32424005
- Full Text :
- https://doi.org/10.1136/gutjnl-2020-321000