(1) Joalland N (2) Quéméner A (3) Deshayes S (4) Humeau R (5) Maillasson M (6) LeBihan H (7) Salama A (8) Fresquet J (9) Remy S (10) Mortier E (11) Blanquart C (12) Guillonneau C (13) Anegon I

Journal for immunotherapy of cancer | Free PMC Article

To inhibit interactions of CSF-1 with CSF-1R and IL-34 with CSF-1R, PTPζ, SDC-1 and TREM2, Joalland et al. generated a soluble fusion protein comprising a mutein (M149K) of the human CSF-1R extracellular domain dimerized by a silenced human IgG1Fc. Mutein CSF-1R-Fc had higher affinity for CSF-­1 and IL-­34 than wild-type CSF-1R-Fc; inhibited CSF-­1R signaling, monocyte viability, and induction of suppressive TAMs by CSF-­1/IL-34-expressing pleural mesothelioma cells better than anti-­IL-­34 and/or anti-CSF-­1 mAbs; and induced lysis of mesothelioma cells by a tumor-specific CD8+ T cell clone in mesothelioma/macrophage spheroids in vitro and in vivo.

Contributed by Paula Hochman

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-1R(M149K)-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-1R(M149K)-Fc or sCSF-1R-Fc wild type control (sCSF-1R(WT)-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-1R(M149K)-Fc trapped with higher affinity than sCSF-1R(WT)-Fc both CSF-1 and IL-34 added in culture and naturally produced in mesothelioma pleural effusions. sCSF-1R(M149K)-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-1R(M149K)-Fc also resulted in higher killing of pleural mesothelioma cells by a tumor-specific CD8(+) T cell clone in mesothelioma/macrophage spheroids. CONCLUSIONS: sCSF-1R(M149K)-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-1R(M149K)-Fc has therapeutic potential vs other therapies under development targeting single components of this complex cytokine pathway involved in cancer.

Author Info: (1) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes UniversitŽ, Nantes, France. (2) LabE

Author Info: (1) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes UniversitŽ, Nantes, France. (2) LabEx IGO, Nantes UniversitŽ, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, UniversitŽ d'Angers, CRCI2NA, University of Nantes, Nantes, France. (3) LabEx IGO, Nantes UniversitŽ, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, UniversitŽ d'Angers, CRCI2NA, University of Nantes, Nantes, France. (4) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes UniversitŽ, Nantes, France. (5) LabEx IGO, Nantes UniversitŽ, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, UniversitŽ d'Angers, CRCI2NA, University of Nantes, Nantes, France. INSERM, CNRS, SFR Bonamy, UMS BioCore, Imp@ct Platform, Nantes UniversitŽ, Centre Hospitalo-Universitaire (CHU) Nantes, Nantes, France. (6) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes UniversitŽ, Nantes, France. (7) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes UniversitŽ, Nantes, France. (8) LabEx IGO, Nantes UniversitŽ, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, UniversitŽ d'Angers, CRCI2NA, University of Nantes, Nantes, France. (9) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. (10) LabEx IGO, Nantes UniversitŽ, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, UniversitŽ d'Angers, CRCI2NA, University of Nantes, Nantes, France. INSERM, CNRS, SFR Bonamy, UMS BioCore, Imp@ct Platform, Nantes UniversitŽ, Centre Hospitalo-Universitaire (CHU) Nantes, Nantes, France. (11) LabEx IGO, Nantes UniversitŽ, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, UniversitŽ d'Angers, CRCI2NA, University of Nantes, Nantes, France. (12) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France ianegon@nantes.inserm.fr carole.guillonneau@univ-nantes.fr. LabEx IGO, Nantes UniversitŽ, Nantes, France. (13) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France ianegon@nantes.inserm.fr carole.guillonneau@univ-nantes.fr. LabEx IGO, Nantes UniversitŽ, Nantes, France.

Citation: J Immunother Cancer 2025 Mar 17 13: Epub03/17/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40101804

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