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Complement Factor H Is an ICOS Ligand Modulating Tregs in the Glioma Microenvironment

Smolag-Klosowska, Karolina I LU orcid ; Olszowka, Jakub LU ; Rosberg, Rebecca LU orcid ; Johansson, Elinn LU ; Marinko, Elisabet LU ; Leandersson, Karin LU orcid ; O'Connell, David J ; Governa, Valeria LU ; Tuysuz, Emre Can LU and Belting, Mattias LU , et al. (2025) In Cancer immunology research 13(1). p.122-138
Abstract

The survival rate of patients with glioma has not significantly increased in recent years despite aggressive treatment and advances in immunotherapy. The limited response to treatments is partially attributed to the immunosuppressive tumor microenvironment, in which regulatory T cells (Treg) play a pivotal role in immunologic tolerance. In this study, we investigated the impact of complement factor H (FH) on Tregs within the glioma microenvironment and found that FH is an ICOS ligand. The binding of FH to this immune checkpoint molecule promoted the survival and function of Tregs and induced the secretion of TGFβ and IL10 while suppressing T-cell proliferation. We further demonstrated that cancer cells in human and mouse gliomas... (More)

The survival rate of patients with glioma has not significantly increased in recent years despite aggressive treatment and advances in immunotherapy. The limited response to treatments is partially attributed to the immunosuppressive tumor microenvironment, in which regulatory T cells (Treg) play a pivotal role in immunologic tolerance. In this study, we investigated the impact of complement factor H (FH) on Tregs within the glioma microenvironment and found that FH is an ICOS ligand. The binding of FH to this immune checkpoint molecule promoted the survival and function of Tregs and induced the secretion of TGFβ and IL10 while suppressing T-cell proliferation. We further demonstrated that cancer cells in human and mouse gliomas directly produce FH. Database investigations revealed that upregulation of FH expression was associated with the presence of Tregs and correlated with worse prognosis for patients with glioma. We confirmed the effect of FH on glioma development in a mouse model, in which FH knockdown was associated with a decrease in the number of ICOS+ Tregs and demonstrated a tendency of prolonged survival (P = 0.064). Because the accumulation of Tregs represents a promising prognostic and therapeutic target, evaluating FH expression should be considered when assessing the effectiveness of and resistance to immunotherapies against glioma.

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Contribution to journal
publication status
published
subject
keywords
Tumor Microenvironment/immunology, T-Lymphocytes, Regulatory/immunology, Animals, Glioma/immunology, Humans, Mice, Inducible T-Cell Co-Stimulator Protein/metabolism, Complement Factor H/metabolism, Brain Neoplasms/immunology, Cell Line, Tumor, Disease Models, Animal, Inducible T-Cell Co-Stimulator Ligand/metabolism, Prognosis, Mice, Inbred C57BL, Ligands
in
Cancer immunology research
volume
13
issue
1
pages
122 - 138
publisher
American Association for Cancer Research
external identifiers
  • scopus:85214888647
  • pmid:39378431
ISSN
2326-6074
DOI
10.1158/2326-6066.CIR-23-1092
language
English
LU publication?
yes
additional info
©2024 The Authors; Published by the American Association for Cancer Research.
id
787088a4-baa3-4118-8b73-079971ae90c0
date added to LUP
2025-02-21 13:31:25
date last changed
2025-07-13 02:32:34
@article{787088a4-baa3-4118-8b73-079971ae90c0,
  abstract     = {{<p>The survival rate of patients with glioma has not significantly increased in recent years despite aggressive treatment and advances in immunotherapy. The limited response to treatments is partially attributed to the immunosuppressive tumor microenvironment, in which regulatory T cells (Treg) play a pivotal role in immunologic tolerance. In this study, we investigated the impact of complement factor H (FH) on Tregs within the glioma microenvironment and found that FH is an ICOS ligand. The binding of FH to this immune checkpoint molecule promoted the survival and function of Tregs and induced the secretion of TGFβ and IL10 while suppressing T-cell proliferation. We further demonstrated that cancer cells in human and mouse gliomas directly produce FH. Database investigations revealed that upregulation of FH expression was associated with the presence of Tregs and correlated with worse prognosis for patients with glioma. We confirmed the effect of FH on glioma development in a mouse model, in which FH knockdown was associated with a decrease in the number of ICOS+ Tregs and demonstrated a tendency of prolonged survival (P = 0.064). Because the accumulation of Tregs represents a promising prognostic and therapeutic target, evaluating FH expression should be considered when assessing the effectiveness of and resistance to immunotherapies against glioma.</p>}},
  author       = {{Smolag-Klosowska, Karolina I and Olszowka, Jakub and Rosberg, Rebecca and Johansson, Elinn and Marinko, Elisabet and Leandersson, Karin and O'Connell, David J and Governa, Valeria and Tuysuz, Emre Can and Belting, Mattias and Pietras, Alexander and Martin, Myriam and Blom, Anna M}},
  issn         = {{2326-6074}},
  keywords     = {{Tumor Microenvironment/immunology; T-Lymphocytes, Regulatory/immunology; Animals; Glioma/immunology; Humans; Mice; Inducible T-Cell Co-Stimulator Protein/metabolism; Complement Factor H/metabolism; Brain Neoplasms/immunology; Cell Line, Tumor; Disease Models, Animal; Inducible T-Cell Co-Stimulator Ligand/metabolism; Prognosis; Mice, Inbred C57BL; Ligands}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{122--138}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Cancer immunology research}},
  title        = {{Complement Factor H Is an ICOS Ligand Modulating Tregs in the Glioma Microenvironment}},
  url          = {{http://dx.doi.org/10.1158/2326-6066.CIR-23-1092}},
  doi          = {{10.1158/2326-6066.CIR-23-1092}},
  volume       = {{13}},
  year         = {{2025}},
}