A1 Refereed original research article in a scientific journal
Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8(+) T-cell Response against Immunosuppressive Tumors
Authors: Viitala M., Virtakoivu R., Tadayon S., Rannikko J., Jalkanen S., Hollmen M.
Publisher: AMER ASSOC CANCER RESEARCH
Publication year: 2019
Journal: Clinical Cancer Research
Journal name in source: CLINICAL CANCER RESEARCH
Journal acronym: CLIN CANCER RES
Volume: 25
Issue: 11
First page : 3289
Last page: 3303
Number of pages: 15
ISSN: 1078-0432
eISSN: 1557-3265
DOI: https://doi.org/10.1158/1078-0432.CCR-18-3016(external)
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/41236195(external)
Purpose: As foremost regulators of cancer-related inflammation and immunotherapeutic resistance, tumor-associated macrophages have garnered major interest as immunotherapeutic drug targets. However, depletory strategies have yielded little benefit in clinical studies to date. An alternative approach is to exploit macrophage plasticity and "reeducate" tumorigenic macrophages toward an immunostimulatory phenotype to activate the host's antitumor immunity.
Experimental Design: We investigated the role of the macrophage scavenger receptor common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1) on tumor growth in multiple mouse cancer models with inflammatory and noninflammatory characteristics by using conditional knockouts, bone marrow chimeras, and cell depletion experiments. In addition, the efficacy of immunotherapeutic Clever-1 blockade as monotherapy or in combination with anti-PD-1 was tested.
Results: Genetic deficiency of macrophage Clever-1 markedly impaired solid tumor growth. This effect was mediated by macrophages that became immunostimulatory in the absence of Clever-1, skewing the suppressive tumor microenvironment toward inflammation and activating endogenous antitumor CD8 thorn T cells. Comparable effects were achieved with immunotherapeutic blockade of Clever-1. Notably, these effects were similar to those achieved by PD-1 checkpoint inhibition. Moreover, combining anti-Clever-1 with anti-PD-1 provided synergistic benefit in aggressive, nonresponsive tumors.
Conclusions: These findings demonstrate the importance of macrophages in mediating antitumor immune responses and support the clinical evaluation of immunotherapeutic Clever-1 blockade as a novel cancer treatment strategy.
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