Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity
| Autor: | Sunita Varsani-Brown, Natalia Moncaut, Michael D. Buck, Enzo Z. Poirier, Ana Cardoso, Stefano Sammicheli, Oliver Gordon, Probir Chakravarty, Naren Srinivasan, Johnathan Canton, Kok Haw Jonathan Lim, Oliver Schulz, Neil C. Rogers, Evangelos Giampazolias, Santiago Zelenay, Caetano Reis e Sousa, Ian Rosewell |
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| Rok vydání: | 2021 |
| Předmět: |
CLEC9A
medicine.medical_treatment T cell Priming (immunology) CD8-Positive T-Lymphocytes Biology Article General Biochemistry Genetics and Molecular Biology F-actin 03 medical and health sciences Cross-Priming 0302 clinical medicine Cancer immunotherapy Antigen Antigens Neoplasm Cell Movement cancer immunity Neoplasms medicine Animals Lectins C-Type Amino Acid Sequence dendritic cells Receptors Immunologic Immune Checkpoint Inhibitors Cytoskeleton Gelsolin cross-presentation Cell Proliferation 030304 developmental biology 0303 health sciences Immunity Cross-presentation Actin cytoskeleton Survival Analysis Actins DNGR-1 3. Good health Cell biology Gene Expression Regulation Neoplastic Mice Inbred C57BL medicine.anatomical_structure Receptors Mitogen Mutation secreted gelsolin 030217 neurology & neurosurgery CD8 Protein Binding |
| Zdroj: | Cell |
| ISSN: | 0092-8674 |
| Popis: | Summary Cross-presentation of antigens from dead tumor cells by type 1 conventional dendritic cells (cDC1s) is thought to underlie priming of anti-cancer CD8+ T cells. cDC1 express high levels of DNGR-1 (a.k.a. CLEC9A), a receptor that binds to F-actin exposed by dead cell debris and promotes cross-presentation of associated antigens. Here, we show that secreted gelsolin (sGSN), an extracellular protein, decreases DNGR-1 binding to F-actin and cross-presentation of dead cell-associated antigens by cDC1s. Mice deficient in sGsn display increased DNGR-1-dependent resistance to transplantable tumors, especially ones expressing neoantigens associated with the actin cytoskeleton, and exhibit greater responsiveness to cancer immunotherapy. In human cancers, lower levels of intratumoral sGSN transcripts, as well as presence of mutations in proteins associated with the actin cytoskeleton, are associated with signatures of anti-cancer immunity and increased patient survival. Our results reveal a natural barrier to cross-presentation of cancer antigens that dampens anti-tumor CD8+ T cell responses. Graphical abstract Highlights • Secreted gelsolin (sGSN) inhibits DNGR-1 binding to F-actin • sGSN dampens DNGR-1-dependent cross-presentation of dead cell-associated antigens • sGSN impairs DNGR-1-dependent cDC1-mediated anti-tumor immunity • Low sGSN expression and mutations in FABPs correlate with cancer patient survival The secreted gelsolin component of the plasma actin-scavenging system impairs the ability of the receptor DNGR-1 to recognize dead cells and selectively dampens cross-presentation of tumor antigens by type 1 dendritic cells, acting as a barrier to anti-tumor immunity. |
| Databáze: | OpenAIRE |
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