CDK1/2/5 inhibition overcomes IFNG-mediated adaptive immune resistance in pancreatic cancer.

Abstract

OBJECTIVE:

Adaptive immune resistance mediated by the cytokine interferon gamma (IFNG) still constitutes a major problem in cancer immunotherapy. We develop strategies for overcoming IFNG-mediated adaptive immune resistance in pancreatic ductal adenocarcinoma cancer (PDAC).

DESIGN:

We screened 429 kinase inhibitors for blocking IFNG-induced immune checkpoint (indoleamine 2,3-dioxygenase 1 (IDO1) and CD274) expression in a human PDAC cell line. We evaluated the ability of the cyclin-dependent kinase (CDK) inhibitor dinaciclib to block IFNG-induced IDO1 and CD274 expression in 24 human and mouse cancer cell lines as well as in primary cancer cells from patients with PDAC or ovarian carcinoma. We tested the effects of dinaciclib on IFNG-induced signal transducer and activator of transcription 1 activation and immunological cell death, and investigated the potential utility of dinaciclib in combination with IFNG for pancreatic cancer therapy in vivo, and compared gene expression levels between human cancer tissues with patient survival times using the Cancer Genome Atlas datasets.

RESULTS:

Pharmacological (using dinaciclib) or genetic (using shRNA or siRNA) inactivation of CDK1/2/5 not only blocks JUN-dependent immune checkpoint expression, but also triggers histone-dependent immunogenic cell death in immortalised or primary cancer cells in response to IFNG. This dual mechanism turns an immunologically 'cold' tumour microenvironment into a 'hot' one, dramatically improving overall survival rates in mouse pancreatic tumour models (subcutaneous, orthotopic and transgenic models). The abnormal expression of CDK1/2/5 and IDO1 was associated with poor patient survival in several cancer types, including PDAC.

CONCLUSION:

CDK1/2/5 kinase activity is essential for IFNG-mediated cancer immunoevasion. CDK1/2/5 inhibition by dinaciclib provides a novel strategy to overcome IFNG-triggered acquired resistance in pancreatic tumour immunity.

• Authors: Jin Huang, Pan Chen, Ke Liu, Jiao Liu, Borong Zhou, Runliu Wu, Qiu Peng, Ze-Xian Liu, Changfeng Li, Guido Kroemer, Michael Lotze, Herbert Zeh, Rui Kang, Daolin Tang
• Journal: Gut (Gut) Vol. 70 Issue 5 Pg. 890-899 (05 2021) ISSN: 1468-3288 [Electronic] England
• PMID: 32816920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• Cd274 protein, mouse
• Cyclic N-Oxides
• Immune Checkpoint Inhibitors
• Indolizines
• Peptide Fragments
• Pyridinium Compounds
• interferon gamma (1-39)
• dinaciclib
• Interferon-gamma
• Cyclin-Dependent Kinase 5
• CDC2 Protein Kinase
• CDK1 protein, human
• CDK2 protein, human
• CDK5 protein, human
• Cdk1 protein, mouse
• Cdk2 protein, mouse
• Cdk5 protein, mouse
• Cyclin-Dependent Kinase 2

Topics

• Adaptive Immunity
• Adenocarcinoma (drug therapy, genetics, immunology)
• Animals
• B7-H1 Antigen (antagonists & inhibitors)
• CDC2 Protein Kinase (antagonists & inhibitors)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, immunology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cyclic N-Oxides (pharmacology)
• Cyclin-Dependent Kinase 2 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 5 (antagonists & inhibitors)
• Gene Expression
• Humans
• Immune Checkpoint Inhibitors (pharmacology)
• Indolizines (pharmacology)
• Interferon-gamma (pharmacology)
• Mice
• Pancreatic Neoplasms (drug therapy, genetics, immunology)
• Peptide Fragments (pharmacology)
• Pyridinium Compounds (pharmacology)
• Signal Transduction
• Survival Rate
• Tumor Microenvironment (drug effects)