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  • Multivalent tyrosine kinase inhibition promotes T cell recruitment to immune-desert gastric cancers by restricting epithelial-mesenchymal transition via tumour-intrinsic IFN-γ signalling

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Original research
Multivalent tyrosine kinase inhibition promotes T cell recruitment to immune-desert gastric cancers by restricting epithelial-mesenchymal transition via tumour-intrinsic IFN-γ signalling
  1. Long Long Cao1,2,3,
  2. Heng Lu2,
  3. Mohammed Soutto2,
  4. Nadeem Bhat2,
  5. Zheng Chen2,4,
  6. Dunfa Peng2,
  7. Ahmed Gomaa2,
  8. Jia Bin Wang1,
  9. Jian Wei Xie1,
  10. Ping Li1,
  11. Chao Hui Zheng1,3,
  12. Sachiyo Nomura5,
  13. Jashodeep Datta2,4,
  14. Nipun Merchant2,4,
  15. Zhi Bin Chen4,6,
  16. Alejandro Villarino4,6,
  17. Alexander Zaika2,4,7,
  18. Chang Ming Huang1,3,
  19. Wael El-Rifai2,4,7
  1. 1 Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
  2. 2 Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
  3. 3 Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
  4. 4 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
  5. 5 Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  6. 6 Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA
  7. 7 Department of Veterans Affairs, Miami Healthcare System, Miami, Florida, USA
  1. Correspondence to Professor Wael El-Rifai, Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; wxe45{at}miami.edu; Professor Chang Ming Huang, Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China; hcmlr2002{at}163.com

Abstract

Objective Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumour-intrinsic and acquired immunotherapy resistance. We developed an immunophenotype-based subtyping of human GC based on immune cells infiltration to develop a novel treatment option.

Design A algorithm was developed to reclassify GC into immune inflamed, excluded and desert subtypes. Bioinformatics, human and mouse GC cell lines, syngeneic murine gastric tumour model, and CTLA4 blockade were used to investigate the immunotherapeutic effects by restricting receptor tyrosine kinase (RTK) signalling in immune desert (ICB-resistant) type GC.

Results Our algorithm restratified subtypes of human GC in public databases and showed that immune desert-type and excluded-type tumours are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signalling was highly enriched in immune desert-type GC, and syngeneic murine tumours exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identified a panel of RTKs as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activated the tumour-intrinsic SNAI1/2-IFN-γ signalling axis and impeded the EMT programme, converting immune desert-type tumours to immune inflamed-type tumours, sensitising these mesenchymal-like ‘cold’ tumours to CTLA4 blockade.

Conclusion Our findings identified potential druggable targets relevant to patient groups, especially for refractory immune desert-type/ ‘cold’ GC. Dovitinib, an RTK inhibitor, sensitised desert-type immune-cold GC to CTLA4 blockade by restricting EMT and recruiting T cells.

  • gastric cancer
  • carcinogenesis
  • cell biology

Data availability statement

Data are available on reasonable request. Most data relevant to the study are included in the article or uploaded as supplemental information. Additional data are available upon reasonable request.

https://doi.org/10.1136/gutjnl-2022-329134

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    Data availability statement

    Data are available on reasonable request. Most data relevant to the study are included in the article or uploaded as supplemental information. Additional data are available upon reasonable request.

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    Footnotes

    • Twitter @DrJashDatta

    • LLC and HL contributed equally.

    • Contributors LLC designed the experiments, analysed the data and wrote the manuscript. HL: designed the in vitro and in vivo experiments, and interpretated the data. SMZ: assisted in in vitro experiments and interpretation of data. MS, AG, ZC and NLB: assisted in in vivo experiments and interpretation of data. DLP, JWX and JBW: designed the immunohistochemistry experiment of human samples and analysed the data. PL and CHZ: collected human samples and their clinicopathological features. JD, AV and AZ: study concept and design, drafting of the manuscript. SN: provided mouse gastric cancer cell lines (YTN2 and YTN16). WE-R and CMH: studied concept and design, supervised the study, troubleshot experimental issues, performed interpretation of data and critically revised the manuscript. WE-R is the gurantator and has the final responsibility for the overall content of this manuscript.

    • Funding This study was supported by grants from the US National Institutes of Health (R01CA249949 and 1R01CA266528) and the US Department of Veterans Affairs (1IK6BX003787 and I01BX001179). The Sylvester Comprehensive Cancer Center supported the use of shared resources (P30CA240139).

    • 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.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.