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Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity
Evangelos Giampazolias1, Oliver Schulz1, Kok Haw Jonathan Lim2
1Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Abstract:
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.
Insights
Secreted gelsolin (sGSN) inhibits anti-cancer immune responses by blocking dendritic cell antigen uptake. Reducing sGSN enhances anti-tumor immunity and immunotherapy effectiveness, revealing a new target for cancer treatment.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Type 1 conventional dendritic cells (cDC1s) are crucial for anti-cancer CD8+ T cell responses via antigen cross-presentation.
- cDC1s utilize the DNGR-1 receptor to bind F-actin on dead cells, facilitating antigen cross-presentation.
- Secreted gelsolin (sGSN) is an extracellular protein with potential roles in immune modulation.
Purpose of the Study:
- To investigate the role of secreted gelsolin (sGSN) in regulating antigen cross-presentation by cDC1s.
- To determine the impact of sGSN on anti-tumor immunity and cancer immunotherapy.
- To explore the clinical relevance of sGSN and actin cytoskeleton-associated proteins in human cancers.
Main Methods:
- Assessed the effect of sGSN on DNGR-1 binding to F-actin and antigen cross-presentation by cDC1s.
- Utilized sGsn-deficient mice to evaluate tumor resistance and immunotherapy response.
- Analyzed human cancer datasets for correlations between sGSN levels, actin cytoskeleton mutations, anti-cancer immunity, and patient survival.
Main Results:
- Secreted gelsolin (sGSN) inhibits DNGR-1-mediated F-actin binding and antigen cross-presentation by cDC1s.
- Mice lacking sGsn exhibited enhanced DNGR-1-dependent resistance to tumors and improved immunotherapy outcomes.
- Low intratumoral sGSN and mutations in actin cytoskeleton proteins correlated with anti-cancer immunity signatures and better survival in human cancers.
Conclusions:
- Secreted gelsolin acts as a natural barrier, dampening anti-tumor CD8+ T cell responses by inhibiting cDC1-mediated antigen cross-presentation.
- Targeting sGSN or modulating actin cytoskeleton interactions presents a potential strategy to enhance cancer immunotherapy.
- Findings highlight the intricate interplay between extracellular proteins, cellular machinery, and anti-tumor immunity.
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