Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity

Cell. 2021 Jul 22;184(15):4016-4031.e22. doi: 10.1016/j.cell.2021.05.021. Epub 2021 Jun 2.

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.

Keywords: CLEC9A; DNGR-1; F-actin; cancer immunity; cross-presentation; dendritic cells; secreted gelsolin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Amino Acid Sequence
  • Animals
  • Antigens, Neoplasm / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cross-Priming / drug effects
  • Cross-Priming / immunology*
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Gelsolin / chemistry
  • Gelsolin / deficiency
  • Gelsolin / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunity* / drug effects
  • Lectins, C-Type / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Protein Binding / drug effects
  • Receptors, Immunologic / metabolism*
  • Receptors, Mitogen / metabolism*
  • Survival Analysis

Substances

  • Actins
  • Antigens, Neoplasm
  • CLEC9a protein, human
  • Clec9a protein, mouse
  • Gelsolin
  • Immune Checkpoint Inhibitors
  • Lectins, C-Type
  • Receptors, Immunologic
  • Receptors, Mitogen