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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Nov 24, 2022 |
| Title |
Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Immune checkpoint blockade (ICB) has significantly improved the prognosis of cancer patients, but the majority experience limited benefit, evidencing the need for new therapeutic approaches. Upregulation of sialic acid-containing glycans, termed hypersialylation, is a common feature of cancer-associated glycosylation, driving disease progression and immune escape via the engagement of Siglec-receptors on tumor-infiltrating immune cells. Here, we show that tumor sialylation correlates with distinct immune states and reduced survival in human cancers. The targeted removal of Siglec-ligands in the tumor microenvironment, using an antibody-sialidase conjugate, enhances anti-tumor immunity and halts tumor progression in several mouse tumor models. Using single-cell RNA sequencing, we reveal desialylation mechanistically to repolarize tumor-associated macrophages (TAMs) and identify Siglec-E on TAMs as the main receptor for hypersialylation. Finally, we show genetic and therapeutic desialylation, as well as loss of Siglec-E, to synergize with ICB. Thus, therapeutic desialylation represents a novel immunotherapeutic approach, shaping macrophage phenotypes and augmenting the adaptive anti-tumor immune response.
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| Overall design |
C57BL/6 mice carrying established B16D5-HER2 tumors were treated with the tumor-targeted sialidase E-301 or its catalytically inactive control variant E-301 LOF, with or without PD-1/CTLA-4 blockade. CD45+ tumor-infiltrating immune cells were sorted from 5 pooled mice 7 days after the initial treatment.
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| Contributor(s) |
Stanczak MA, Sanin DE, Pearce EL, Läubli H |
| Citation(s) |
36322632 |
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| Submission date |
Jul 13, 2022 |
| Last update date |
Nov 24, 2022 |
| Contact name |
Immunometabolism Department |
| E-mail(s) |
jcurti29@jhmi.edu
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| Organization name |
Johns Hopkins University
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| Department |
Immunometabolism
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| Street address |
1650 Orleans Street
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| City |
Baltimore |
| State/province |
Maryland |
| ZIP/Postal code |
21287 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (5)
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| Relations |
| BioProject |
PRJNA858443 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE208133_RAW.tar |
263.2 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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