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

Jin Huang1,2, Pan Chen3, Ke Liu4,5

  • 1The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.

Gut
|August 21, 2020
PubMed
Abstract

Insights

Inhibiting CDK1/2/5 with dinaciclib blocks interferon gamma (IFNG)-induced immune checkpoints and triggers cancer cell death. This strategy overcomes IFNG-mediated resistance in pancreatic cancer, improving survival in models.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Interferon gamma (IFNG) mediated adaptive immune resistance is a key challenge in cancer immunotherapy, particularly in pancreatic ductal adenocarcinoma (PDAC).
  • Strategies are needed to overcome this resistance and enhance the efficacy of cancer treatments.

Purpose of the Study:

  • To identify strategies for overcoming IFNG-mediated adaptive immune resistance in pancreatic cancer.
  • To evaluate the potential of cyclin-dependent kinase (CDK) inhibitors, specifically dinaciclib, in combination with IFNG for pancreatic cancer therapy.

Main Methods:

  • Screened 429 kinase inhibitors for blocking IFNG-induced immune checkpoint expression (IDO1, CD274) in PDAC cells.
  • Evaluated dinaciclib's efficacy in blocking IFNG-induced IDO1 and CD274 expression across various cancer cell lines and primary patient cells.
  • Assessed dinaciclib's effects on IFNG-induced STAT1 activation and immunogenic cell death, and tested its therapeutic potential in vivo using pancreatic cancer models.

Main Results:

  • Inactivation of CDK1/2/5 by dinaciclib or genetic methods blocked JUN-dependent immune checkpoint expression and triggered histone-dependent immunogenic cell death in response to IFNG.
  • This dual mechanism converted 'cold' tumors to 'hot' tumors, significantly improving survival rates in mouse models of pancreatic cancer.
  • Abnormal expression of CDK1/2/5 and IDO1 correlated with poor patient survival in multiple cancer types, including PDAC.

Conclusions:

  • CDK1/2/5 kinase activity is crucial for IFNG-mediated cancer immunoevasion.
  • Dinaciclib-mediated inhibition of CDK1/2/5 presents a novel strategy to overcome IFNG-triggered acquired resistance in pancreatic tumor immunity.
Keywords:
cell deathimmunologypancreatic cancer

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