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| Status |
Public on Jul 03, 2024 |
| Title |
Tumor-derived kynurenine induces Siglec-15 expression and promotes CD8+T cell exhaustion in oral squamous cell carcinoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Metabolic deregulation and immune escape are pivotal hallmarks of cancer; however, the profile of metabolic reprogramming in oral squamous cell carcinoma (OSCC) and how it drives immune escape remain unclear. We identified significant metabolic disorders in OSCC. Amino acid metabolism, especially tryptophan/kynurenine metabolism, was altered. Here, we found that kynurenine promotes migration, invasion, and proliferation in vitro and in vivo. In addition, most immune checkpoints were upregulated in patients with high kynurenine levels. We then identified that kynurenine can promote Siglec-15 expression via AhR activation. Furthermore, tumor-derived kynurenine can directly exhaust CD8+ T cells, whereas blocking of kynurenine transporters reversed this effect. Moreover, we found that ectopic expression of Siglec-15 can promote immune escape in tumor microenvironment (TME) by suppressing T cell infiltration and inducing CD8+ T cell exhaustion in vivo, while targeting AhR reduces kynurenine-mediated immune escape. Finally, we design NH2-MSNs nanoparticles to deliver Siglec-15 small interfering RNA, which successfully remodels the TME and enhances anti-PD-1 efficacy in tumor-bearing immunocompetent mice. Clinically, Siglec-15 expression is correlated with AhR expression and high infiltration of exhausted CD8+ T cells. These findings reveal that the Kyn/AhR/Siglec-15 signaling pathway is a novel immunometabolism mechanism in OSCC, thus opening a new therapeutic avenue for metabolic immunotherapy.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for 69 pairs of oral squamous cell carcinoma and paracancerous tissues
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| Contributor(s) |
Zhang X, Shi J, Jin S, Wang R, Li M, Zhang Z, Yang X, Ma H |
| Citation(s) |
38734931 |
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| Submission date |
Jan 11, 2023 |
| Last update date |
Jul 03, 2024 |
| Contact name |
Hailong Ma |
| E-mail(s) |
mahl21@sjtu.edu.cn
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| Organization name |
Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine
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| Street address |
Zhizaoju Rd
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| City |
Shanghai |
| ZIP/Postal code |
200011 |
| Country |
China |
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| Platforms (1) |
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| Samples (138)
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| Relations |
| BioProject |
PRJNA923002 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE222673_raw_counts_anno.txt.gz |
6.1 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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