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| Status |
Public on Dec 26, 2018 |
| Title |
Self-associated molecular patterns mediate cancer immune evasion by engagement of Siglec receptors |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Cancer immunotherapy targeting inhibitory receptors on T cells has changed the landscape of oncological practice, but most patients do not respond to current approaches. Thus, new targets on T cells for cancer immunotherapy are needed. CD33-related Siglecs are pattern recognition immune receptors binding to a broad range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) to dampen unwanted immune responses against self. Naïve T cells in humans have very low levels of inhibitory Siglec expression. Here, we show Siglec-9 in non-small cell lung cancer (NSCLC) are significantly upregulated on tumor-infiltrating T cells. These findings were confirmed in other tumor types including colorectal cancer, and ovarian cancer. Characterization of Siglec-9 expressing T cells showed a co-expression of inhibitory receptors including PD-1 and a distinct phenotype with increased cytokine production upon restimulation, compared to Siglec negative T cells. Functional analysis by reduction of sialoglycan-SAMPs on tumor cells in vitro and in vivo demonstrated an increased tumor cell killing and an inhibition of tumor growth. Overexpression of inhibitory Siglecs on T cells enhanced tumor growth in mice and exchange of inhibitory Siglecs on mouse T cells with an activating Siglec enhanced anti-cancer immunity. Increased T cell expression of Siglec-9 in NSCLC patients also correlated with survival, and analysis of Siglec-9 polymorphisms showed an association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as potential new target to improve T cell activation and cancer immunotherapy.
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| Overall design |
Six non-small cell lung cancer tumor infiltrating CD8+ T cells (CD45+ CD3+ CD8+ CD4-) were sorted by flow cytometry according to their Siglec9 staining into Siglec9+ and Siglec9- samples.
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| Contributor(s) |
Stanczak MA, Trefny MP, Thommen D, Tzankov A, Tietze L, Lardinois D, Heinzelmann-Schwarz V, Zippelius A, Läubli H |
| Citation(s) |
30130255 |
| |
| Submission date |
Jun 04, 2018 |
| Last update date |
Mar 26, 2019 |
| Contact name |
Heinz Läubli |
| E-mail(s) |
heinz.laeubli@unibas.ch
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| Phone |
+41 61 556 5212
|
| Organization name |
University of Basel
|
| Department |
Department of Biomedicine
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| Lab |
Medical Oncology and Cancer Immunology
|
| Street address |
Hebelstrasse 20
|
| City |
Basel |
| ZIP/Postal code |
4031 |
| Country |
Switzerland |
| |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA474508 |
| SRA |
SRP149715 |
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