A1 Refereed original research article in a scientific journal
Secreted Clever-1 modulates T cell responses and impacts cancer immunotherapy efficacy
Authors: Prince, Stuart; Viitala, Miro; Sjoroos, Riikka; Bendes, Abris a.; Rannikko, Jenna H.; Patten, Daniel A.; di Benedetto, Ilaria; Turpin, Rita; Ylitalo, Arno; Tyni, Laura; Figueiredo, Carlos R.; Bostrom, Pia; Koskivuo, Ilkka; Salminen, Tiina A.; Shetty, Shishir; Hollmen, Maija
Publisher: Ivyspring International Publisher
Publishing place: LAKE HAVEN
Publication year: 2025
Journal: Theranostics
Journal name in source: Theranostics
Journal acronym: THERANOSTICS
Volume: 15
Issue: 15
First page : 7501
Last page: 7527
Number of pages: 27
ISSN: 1838-7640
DOI: https://doi.org/10.7150/thno.110544
Web address : https://doi.org/10.7150/thno.110544
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/499435526
Rationale: Clever-1 is a multifunctional scavenger receptor that promotes immunosuppressive activity in macrophages, contributing to tumor immune evasion. Its high expression correlates with resistance to immune checkpoint inhibitors, and co-targeting Clever-1 with anti-PD-1 enhances therapeutic efficacy in refractory tumor models. The humanized anti-Clever-1 IgG4 antibody, bexmarilimab, is under clinical investigation for treating solid tumors (NCT03733990) and hematological malignancies (NCT05428969). Methods: To assess the impact of Clever-1 in cancer, we analyzed plasma samples from breast cancer patients (n=139) and bexmarilimab-treated clinical trial participants (n=193) using TRFIA-based ELISA to quantify secreted Clever-1 (sClever-1). A recombinant sClever-1 protein was produced and characterized biophysically. Functional assays, including flow cytometry, Western blotting, T cell activation, and Jurkat reporter systems, were used to assess interactions with T cells. Mechanistic studies involved extracellular vesicle isolation, pulldown assays, and mass spectrometry. Inhibitor studies and patient-derived tumor explants were used to evaluate the immunomodulatory impact of sClever-1 and its effect on anti-PD-1 responses. Results: sClever-1 was significantly enriched in the plasma of cancer patients and reduced following bexmarilimab treatment. Its release was induced by IFN gamma/LPS via serine protease-dependent cleavage. The recombinant sClever-1 bound selectively to activated T cells via mannose-6-phosphate-mediated interaction with IGF2R, impairing TCR signaling and Th1 expansion. sClever-1 was also associated with macrophage-derived extracellular vesicles and contributed to T cell tolerance and reduced anti-PD-1 efficacy. In tumor explants, sClever-1 bound to activated CD4+and CD8+ T cells and increased TGF beta secretion. Conclusions: These findings identify sClever-1 as a previously unrecognized, immunosuppressive mediator in cancer that operates independently of cellular Clever-1 expression. sClever-1 may serve as both a therapeutic target and biomarker to guide immunotherapy strategies.
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Funding information in the publication:
This study was funded by Cancer Research UK (CRUK) (to DAP and SS), Advanced Clinician Scientist Fellowship (C53575/A29959) (to SS), the Magnus Ehrnrooth Foundation, Tor, Joe and Pentti Borg Memorial Foundation and Sigrid Jusélius Foundation (all to TAS), the Research Council of Finland, Cancer Foundations, and Sigrid Jusélius Foundation (all to MH). Faron Pharmaceuticals sponsored the MATINS trial and supported the research via a contract research agreement. This paper represents independent research supported by the NIHR Birmingham Biomedical Research Center at the University Hospitals Birmingham NHS Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.
