Intratumoral Myeloid Cells Regulate Responsiveness and Resistance to Antiangiogenic Therapy

•Sensitivity to VEGF/VEGFR inhibition is driven by myeloid-cell-derived CXCL14•Myeloid PI3K activation overrides sensitivity and promotes angiogenic relapse•Myeloid-cell oscillation in tumors maintains resistance to antiangiogenic therapy•Inhibition of myeloid PI3K activity overcomes resistance to antiangiogenic therapy

SummaryAntiangiogenic therapy is commonly used in the clinic, but its beneficial effects are short-lived, leading to tumor relapse within months. Here, we found that the efficacy of angiogenic inhibitors targeting the VEGF/VEGFR pathway was dependent on induction of the angiostatic and immune-stimulatory chemokine CXCL14 in mouse models of pancreatic neuroendocrine and mammary tumors. In response, tumors reinitiated angiogenesis and immune suppression by activating PI3K signaling in all CD11b+ cells, rendering tumors nonresponsive to VEGF/VEGFR inhibition. Adaptive resistance was also associated with an increase in Gr1+CD11b+ cells, but targeting Gr1+ cells was not sufficient to further sensitize angiogenic blockade because tumor-associated macrophages (TAMs) would compensate for the lack of such cells and vice versa, leading to an oscillating pattern of distinct immune-cell populations. However, PI3K inhibition in CD11b+ myeloid cells generated an enduring angiostatic and immune-stimulatory environment in which antiangiogenic therapy remained efficient.

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