CSF1R INHIBITION RETARDS MESOTHELIOMA PROGRESSION AND AMPLIFIES CHECKPOINT THERAPY

PURPOSE: Tumor associated macrophages (TAMs) present the dominant innate immune population of the inflammatory malignant pleural mesothelioma (MPM) infiltrate. M1 macrophages exert a direct tumoricidal activity, orchestrate effective anti-tumor responses executed by CD8+ lymphocytes, while M2 macrophages are programmed by the tumors to actively serve for their progression. CSF1R activation confers a pro-tumor M2 phenotype of macrophages while its inhibition polarizes TAMs towards an anti-tumor M1 phenotype. CSF1/CSF1R signaling can therefore impact both tumor-related innate immune responses and tumor cell growth and might present an interesting therapeutic target for MPM. We hypothesized that pharmacological targeting of CSF1R would abrogate experimental MPM growth by reprogramming pro-tumor immune responses. We also hypothesized that CSF1R inhibition would synergistically act with immune checkpoint therapeutic regimens. METHODS: Our hypothesis was tested in syngeneic and orthotopic AE17 and ΑΒ1 murine mesothelioma models. RESULTS: The CSF1R inhibitor (BLZ945) abrogated MPM tumor progression and associated pleural effusion formation. Tumors of BLZ945-treated mice presented reduced CSF1R+ M2 macrophages and enhanced dendritic cell activation compared to control. Additionally, CSF1R inhibition stimulated CD8 lymphocyte activation in tumors. A compensatory PDL-1 upregulation was witnessed in macrophages and DCs. We therefore examined the synergistic advantage of combined anti-CSF1R and anti-PDL1 treatment in mesothelioma progression. Dual therapy significantly retarded MPM progression compared to monotherapies. CONCLUSIONS: CSF1R inhibition substantially abrogates MPM progression affecting tumor growth and tumor-associated inflammation and significantly enhances the effect of an anti-PDL1 drug. CLINICAL IMPLICATIONS: Current results are providing with important preclinical data of CSF1R inhibition in mesothelioma treatment and synergy with anti-PDL1.