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Intratumoral Myeloid Cells Regulate Responsiveness and Resistance to Antiangiogenic Therapy

2015; Cell Press; Volume: 11; Issue: 4 Linguagem: Inglês

10.1016/j.celrep.2015.03.055

2639-1856

Lee B. Rivera, David Meyronet, Valérie Hervieu, Mitchell J. Frederick, Emily K. Bergsland, Gabriele Bergers,

Chemokine receptors and signaling

Antiangiogenic 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.