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  • Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment

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Original research
Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment
  1. Yibo Fan1,
  2. Yuan Li2,
  3. Xiaodan Yao1,
  4. Jiangkang Jin1,
  5. Ailing Scott1,
  6. Bovey Liu3,
  7. Shan Wang3,
  8. Longfei Huo1,
  9. Ying Wang1,
  10. Ruiping Wang4,
  11. Melissa Pool Pizzi1,
  12. Lang Ma1,
  13. Shan Shao1,
  14. Matheus Sewastjanow-Silva1,
  15. Rebecca Waters5,
  16. Deyali Chatterjee5,
  17. Bin Liu6,
  18. Namita Shanbhag1,
  19. Guang Peng7,
  20. George Adrian Calin8,
  21. Pawel Karol Mazur9,
  22. Samir M Hanash7,
  23. Jo Ishizawa10,
  24. Yuki Hirata11,
  25. Osamu Nagano12,
  26. Zhenning Wang2,
  27. Linghua Wang4,
  28. Wa Xian3,
  29. Frank McKeon3,
  30. Jaffer A Ajani1,
  31. Shumei Song1
  1. 1 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2 Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, PR China
  3. 3 Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
  4. 4 Departments of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  5. 5 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  6. 6 Department of Epigenet & Mol Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  7. 7 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  8. 8 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  9. 9 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  10. 10 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  11. 11 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  12. 12 Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan
  1. Correspondence to Dr Shumei Song, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; ssong{at}mdanderson.org; Dr Jaffer A Ajani, Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; jajani{at}mdanderson.org; Dr Jaffer A Ajani, Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; jajani{at}mdanderson.org

Abstract

Objective Many cancers engage embryonic genes for rapid growth and evading the immune system. SOX9 has been upregulated in many tumours, yet the role of SOX9 in mediating immunosuppressive tumour microenvironment is unclear. Here, we aim to dissect the role of SOX9-mediated cancer stemness attributes and immunosuppressive microenvironment in advanced gastric adenocarcinoma (GAC) for novel therapeutic discoveries.

Methods Bulk RNAseq/scRNA-seq, patient-derived cells/models and extensive functional studies were used to identify the expression and functions of SOX9 and its target genes in vitro and in vivo. Immune responses were studied in PBMCs or CD45+ immune cells cocultured with tumour cells with SOX9high or knockout and the KP-Luc2 syngeneic models were used for efficacy of combinations.

Results SOX9 is one of the most upregulated SOX genes in GAC and highly expressed in primary and metastatic tissues and associated with poor prognosis. Depletion of SOX9 in patient-derived GAC cells significantly decreased cancer stemness attributes, tumour formation and metastases and consistently increased CD8+ T cell responses when cocultured with PBMCs/CD45+ cells from GAC patients. RNA sequencing identified the leukaemia inhibitory factor (LIF) as the top secreted molecule regulated by SOX9 in tumour cells and was enriched in malignant ascites and mediated SOX9-induced M2 macrophage repolarisation and inhibited T cell function.

Conclusion Epithelial SOX9 is critical in suppressing CD8+ T cell responses and modified macrophage function in GAC through the paracrine LIF factor. Cotargeting LIF/LIFR and CSF1R has great potential in targeting SOX9-mediated cancer stemness, T cell immunosuppression and metastases suggesting the novel combination therapy against advanced GAC.

  • GASTRIC CANCER
  • GENE REGULATION
  • IMMUNOTHERAPY
  • MOLECULAR ONCOLOGY
  • STEM CELLS

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Data available on request.

https://doi.org/10.1136/gutjnl-2021-326581

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. Data available on request.

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    Footnotes

    • Correction notice This article has been corrected since it published Online First. The supplementary files have been updated.

    • Contributors All authors are responsible for the overall content as the guarantors. Conception and design: SS and JAA; development of methodology: YF, XY, YL, JJ, BL and SW; acquisition of data (performed experiments, analysed data, acquired and managed patients, provided facilities, cell lines and TMA, etc): YF, XY, YL, JJ, BL, SW, AS, LH, LM, MPP, YW, RW, SS, MS-S, NS, RW, DC, GP, GC, PKM, SMH, JI, YH, ON, ZW, LW, WX, FM, JAA and SS. Analysis and interpretation of data (eg, statistical analysis, biostatistics and computational analysis): YF, BL, SW, LW, BL, RW, WX, FM, JAA and SS; writing, review and/or revision of the manuscript: YF, JAA and SS. Administrative, technical or material support (ie, reporting or organising data, research materials, constructing databases): JI, YH, ON, LW and JAA and SS. Study supervision: SS. Other (financial support): JAA and SS.

    • Funding This work was supported by Public Health Service Grant DF56338, which supports the Texas Medical Center Digestive Diseases Center (SS); an MD Anderson Institutional Research Grant (2021-00059328 to S. Song); and grants from Department of Defense (CA160433, CA170906 and CA210457 to SS and CA160445, CA200990 and CA210439 to JAA); and the National Institutes of Health (CA129906, CA138671 and CA172741 to JAA). Supported in part by the Caporella family, the Park family, the Dallas family, the Dio family, the Frankel family, the Kushner family, the Kohn family, the Smith family, anonymous donor, the McNeil family, the Stupid Strong Foundation (Dallas, Texas) and the Gastric Cancer Foundation (San Francisco, California).

    • 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.