Article Text
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.
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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.
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.
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