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GI cancer
Original research
CDK1/2/5 inhibition overcomes IFNG-mediated adaptive immune resistance in pancreatic cancer
  1. Jin Huang1,2,
  2. Pan Chen3,
  3. Ke Liu4,5,
  4. Jiao Liu1,
  5. Borong Zhou1,
  6. Runliu Wu5,
  7. Qiu Peng6,
  8. Ze-Xian Liu7,
  9. Changfeng Li8,
  10. Guido Kroemer9,10,11,12,13,
  11. Michael Lotze14,
  12. Herbert Zeh5,
  13. Rui Kang5,
  14. Daolin Tang1,5
  1. 1 The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
  2. 2 Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
  3. 3 Department of Hepatobiliary Surgery, Hunan Cancer Hospital, Changsha, Hunan, China
  4. 4 Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
  5. 5 Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
  6. 6 Cancer Research Institute, Central South University, Changsha, Hunan, China
  7. 7 Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
  8. 8 Endoscopy Center, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
  9. 9 Equipe Labellisée Par la Ligue Contre le Cancer, Université Paris Descartes, Paris, Île-de-France, France
  10. 10 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
  11. 11 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
  12. 12 Suzhou Institute for Systems Biology, Chinese Academy of Sciences, Suzhou, China
  13. 13 Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
  14. 14 Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  1. Correspondence to Dr Daolin Tang, Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA; daolin.tang{at}utsouthwestern.edu; Dr Rui Kang, Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA; rui.kang{at}utsouthwestern.edu

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.

  • pancreatic cancer
  • immunology
  • cell death

https://doi.org/10.1136/gutjnl-2019-320441

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    Footnotes

    • JH, PC and KL contributed equally.

    • Contributors DT and RK designed the experiments. JH, PC, KL, JL, BZ, RW, QP, CL, Z-XL and DT conducted the experiments. DT wrote the paper. GK, HZ and ML assisted in data interpretation and edited the manuscript.

    • Funding JL is supported by grants from the National Natural Science Foundation of China (31671435, 81400132 and 81772508). CL is supported by a grant from the National Natural Science Foundation of China (81872323).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.