Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8+ T Cell Response Against Immunosuppressive Tumors

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 towards an immunostimulatory phenotype to activate the host's antitumor immunity. Experimental Design: We investigated the role of macrophage scavenger receptor Clever-1 on tumor growth in multiple mouse cancer models with inflammatory and non-inflammatory characteristics by using conditional knockouts, bone marrow chimeras and cell depletion experiments. In addition, the efficacy of immunotherapeutic Clever-1 blockage 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 towards inflammation and activating endogenous antitumor CD8+ 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, non-responsive tumors. Conclusions: These findings demonstrate the importance of macrophages in mediating anti-tumor immune responses and support the clinical evaluation of immunotherapeutic Clever-1 blockade as a novel cancer treatment strategy.

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