New soluble CSF-1R-dimeric mutein with enhanced trapping of both CSF-1 and IL-34 reduces suppressive tumor-associated macrophages in pleural mesothelioma

Our plain-English summary of New soluble CSF-1R-dimeric mutein with enhanced trapping of both CSF-1 and IL-34 reduces suppressive tumor-associated macrophages in pleural mesothelioma, by N. Joalland, A. Quéméner, S. Deshayes, et al (Journal for Immunotherapy of Cancer, 2025).

The study

• Authors: N. Joalland, A. Quéméner, S. Deshayes, R. Humeau, M. Maillasson, H. LeBihan, A. Salama, J. Fresquet, S. Remy, E. Mortier, C. Blanquart, C. Guillonneau, I. Anegon
• Journal: Journal for Immunotherapy of Cancer
• Published: 2025;13(3)
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Colony stimulating factor-1 receptor (CSF-1R) and its ligands CSF-1 and interleukin (IL)-34 have tumorigenic effects through both induction of suppressive macrophages, and survival/proliferation of tumor cells. In addition, the IL-34 tumorigenic effect can also be mediated by its other receptors, protein-tyrosine phosphatase zeta, Syndecan-1 (CD138) and triggering receptor expressed on myeloid cells 2. Small tyrosine kinase inhibitors are used to block CSF-1R signaling but lack specificity. Neutralizing anti-CSF-1 and/or IL-34 antibodies have been proposed, but their effects are limited. Thus, there is a need for a more specific and yet integrative approach.

Methods: A human mutated form of the extracellular portion of CSF-1R was in silico modelized to trap both IL-34 and CSF-1 with higher affinity than the wild-type CSF-1R by replacing the methionine residue at position 149 with a Lysine (M149K). The extracellular portion of the mutated CSF-1R M149K was dimerized using the immunoglobulin Fc sequence of a silenced human IgG1 (sCSF-1RM149K-Fc). Signaling through CSF-1R, survival of monocytes and differentiation of suppressive macrophages were analyzed using pleural mesothelioma patient's samples and mesothelioma/macrophage spheroids in vitro and in vivo in the presence of sCSF-1RM149K-Fc or sCSF-1R-Fc wild type control (sCSF-1RWT-Fc).

Results: We defined that the D1 to D5 domains of the extracellular portion of CSF-1R were required for efficient binding to IL-34 and CSF-1. The mutein sCSF-1RM149K-Fc trapped with higher affinity than sCSF-1RWT-Fc both CSF-1 and IL-34 added in culture and naturally produced in mesothelioma pleural effusions. sCSF-1RM149K-Fc inhibited CSF-1R signaling, survival and differentiation of human suppressive macrophage in vitro and in vivo induced by pleural mesothelioma cells. Neutralization of IL-34 and CSF-1 by sCSF-1RM149K-Fc also resulted in higher killing of pleural mesothelioma cells by a tumor-specific CD8+ T cell clone in mesothelioma/macrophage spheroids.

Conclusions: sCSF-1RM149K-Fc efficiently traps both CSF-1 and IL-34 and inhibits CSF-1R signaling, monocyte survival and suppressive macrophage differentiation induced by pleural mesothelioma cells producing CSF-1 and IL-34, as well as restores cytotoxic T-cell responses. sCSF-1RM149K-Fc has therapeutic potential vs other therapies under development targeting single components of this complex cytokine pathway involved in cancer.

© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

In plain English

This laboratory study described the design and testing of a new soluble, dimeric form of the human colony stimulating factor-1 receptor (CSF-1R) with a single amino acid change (methionine 149 to lysine) fused to a silenced human IgG1 Fc (sCSF-1RM149K-Fc), compared with the wild-type version (sCSF-1RWT-Fc) and with neutralizing anti-CSF-1 and anti-IL-34 antibodies. Work was done in cell lines, monocytes from healthy donors, pleural effusions from patients with pleural mesothelioma, mesothelioma/monocyte spheroids, and immunodeficient mice bearing Meso34 tumors. The authors reported that the dimeric D1-D5 form blocked Akt phosphorylation (IC50 3.4 nM for IL-34, 5.6 nM for CSF-1), that the mutein bound both cytokines with higher affinity than wild type, reduced monocyte survival more than wild type or the antibodies, and restored cytotoxic CD8+ T-cell killing of mesothelioma cells in spheroids. In mice given an injection of human monocytes into the tumor, live human CD45+CD14+ macrophages recovered from the tumors three days later fell by about 45% with the mutein (p less than 0.05). The authors concluded the molecule has therapeutic potential.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: in silico protein design plus in vitro cell and spheroid experiments and an in vivo mouse xenograft experiment
• Who was studied: Human monocytic THP-1 and mouse WM266.4 cell lines, Meso13 and Meso34 pleural mesothelioma cell lines, monocytes from healthy blood donors (Nantes, France), pleural effusions from untreated patients with pleural mesothelioma, and NSG immunodeficient mice bearing Meso34 tumors
• Exposure: Not an exposure study; the agents tested were the mutated soluble dimeric receptor sCSF-1RM149K-Fc, the wild-type sCSF-1RWT-Fc, monomeric and dimeric D1-D3 and D1-D5 forms, neutralizing anti-CSF-1 and anti-IL-34 antibodies, and the CSF-1R tyrosine kinase inhibitor GW2580, against recombinant CSF-1 and IL-34
• Main results:
  • The dimeric D1-D5 soluble receptor inhibited Akt phosphorylation induced by IL-34 (IC50 3.4 nM) and by CSF-1 (IC50 5.6 nM), while the dimeric D1-D3 form did not inhibit the IL-34-induced signal and inhibited the CSF-1-induced one with IC50 15.8 nM
  • Surface plasmon resonance showed higher affinity of the mutein than the wild type: KD 3 versus 8 nM for IL-34 and 2 versus 4 nM for CSF-1
  • In the monocyte viability test with donor monocytes, the mutein neutralized IL-34 and CSF-1 better than wild type (IC50s 8 and 6 nM versus 12 and 16 nM)
  • In mesothelioma pleural effusions, all contained CSF-1 but not all contained IL-34; the mutein inhibited monocyte survival better than the wild-type form in every sample, and the neutralizing antibodies showed little effect
  • In Meso34/monocyte spheroids, macrophages inhibited about 50% of the cytotoxic activity of an HLA-A*0201/MUC1-specific CD8+ T-cell clone; activity was restored to around 80% with the wild-type form and 100% with the mutein
  • In mice whose Meso34 tumors were injected with human monocytes, human CD45+CD14+ macrophages measured in the tumors three days later fell by approximately 30% with the wild-type form (non-significant) and approximately 45% with the mutein (p less than 0.05)
• The authors' conclusion: The authors concluded that the mutein traps both CSF-1 and IL-34, inhibits CSF-1R signaling, monocyte survival and suppressive macrophage differentiation, restores cytotoxic T-cell responses, and has therapeutic potential in at least some cancers

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Macrophage, Pleural Mesothelioma, Tyrosine Kinase Inhibitor, Mesothelioma, Pleural Effusion, Cytokine.

Related studies

• Involvement of the M-CSF/IL-34/CSF-1R pathway in malignant pleural mesothelioma — T. Blondy, S.M. d'Almeida, et al. (2020)
• Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation — M. Cioce, C. Canino, et al. (2014)
• Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy — F. Dammeijer, L.A. Lievense, et al. (2017)
• Prognostic Significance of B7-H3 Expression and CD163+ Tumor-Associated Macrophage Infiltration in Mesothelioma — T. Koç, R.O. Yüceer, et al. (2026)
• Defining and targeting tumor-associated macrophages in malignant mesothelioma — L. Wu, M. Kohno, et al. (2023)
• Microspheres targeted with a mesothelin antibody and loaded with doxorubicin reduce tumor volume of human mesotheliomas in xenografts — S.L. Macura, J.L. Steinbacher, et al. (2013)

Browse more research in Journal for Immunotherapy of Cancer, or return to medical research.