Abstract
BackgroundMetronomic cyclophosphamide given on an intermittent, 6-day repeating schedule, but not on an exposure dose-equivalent daily schedule, activates an anti-tumor innate immune response that leads to major regression of large implanted gliomas, without anti-angiogenesis.Methods and approachMice bearing implanted 9L gliomas were used to investigate the effects of this 6-day repeating, immunogenic cyclophosphamide schedule on myeloid-derived suppressor cells, which are pro-angiogenic and can inhibit anti-tumor immunity, and to elucidate the mechanism whereby the innate immune cell-dependent tumor regression response to metronomic cyclophosphamide treatment is blocked by several anti-angiogenic receptor tyrosine kinase inhibitors.ResultsIntermittent metronomic cyclophosphamide scheduling strongly increased glioma-associated CD11b+ immune cells but not CD11b+Gr1+ myeloid-derived suppressor cells, while bone marrow and spleen reservoirs of the suppressor cells were decreased. The inhibition of immune cell recruitment and tumor regression by anti-angiogenic receptor tyrosine kinase inhibitors, previously observed in several brain tumor models, was recapitulated in the 9L tumor model with the VEGFR2-specific inhibitory monoclonal antibody DC101 (p < 0.01), implicating VEGFR2 signaling as an essential step in metronomic cyclophosphamide-stimulated immune cell recruitment. In contrast, sorafenib, a multi-receptor tyrosine kinase inhibitor with comparatively weak VEGF receptor phosphorylation inhibitory activity, was strongly anti-angiogenic but did not block metronomic cyclophosphamide-induced innate immunity or tumor regression (p > 0.05).ConclusionsThe interference by receptor tyrosine kinase inhibitors in the immunogenic actions of intermittent metronomic chemotherapy is not a consequence of anti-angiogenesis per se, as demonstrated in an implanted 9L tumor model. Furthermore, this undesirable interaction with tyrosine kinase inhibitors can be avoided by using anti-angiogenic drugs that spare the VEGFR2 pathway.
Highlights
Metronomic cyclophosphamide given on an intermittent, 6-day repeating schedule, but not on an exposure dose-equivalent daily schedule, activates an anti-tumor innate immune response that leads to major regression of large implanted gliomas, without anti-angiogenesis
Our findings show that sorafenib is highly antiangiogenic, yet it does not interfere with tumor recruitment of innate immune cells or metronomic CPA-induced tumor regression, supporting the conclusion that inhibition of innate immune cell recruitment is not an intrinsic feature of tumor anti-angiogenesis
Given the ability of Myeloid-derived suppressor cell (MDSC) to suppress natural killer (NK) cell activity [22], which contributes functionally to metronomic CPA-induced tumor regression [10], we investigated whether MDSCs are recruited into CPA-treated tumors, where they could counter the innate immune response to metronomic chemotherapy
Summary
Metronomic cyclophosphamide given on an intermittent, 6-day repeating schedule, but not on an exposure dose-equivalent daily schedule, activates an anti-tumor innate immune response that leads to major regression of large implanted gliomas, without anti-angiogenesis. CPA administered on an intermittent, every 6-day metronomic schedule stimulates tumor recruitment of macrophages, natural killer (NK) cells, and dendritic cells with regression of large established tumors, as seen in several implanted glioma models [10] This potent innate anti-tumor immune response is not achieved using a traditional maximum tolerated dose schedule [10], nor is it seen using an AUC-equivalent daily low dose metronomic CPA schedule [9] that models daily metronomic schedules commonly used in the clinic [2,3]
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