Intratumoral Myeloid Cells Regulate Responsiveness and Resistance to Antiangiogenic Therapy
Lee B. Rivera,
David Meyronet,
Valérie Hervieu,
Mitchell J. Frederick,
Emily Bergsland,
Gabriele Bergers
Affiliations
Lee B. Rivera
Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
David Meyronet
Université Lyon 1, Centre de Pathologie et Neuropathologie Est, Hospices Civils de Lyon, Bron Cedex 69677, France
Valérie Hervieu
Université Lyon 1, Service d’Anatomie Pathologique, Hôpital Édouard Herriot, Hospices Civils de Lyon, Lyon Cedex 69003, France
Mitchell J. Frederick
Department of Head and Neck Surgery, Research Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Emily Bergsland
Department of Medicine, UCSF Mount Zion Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
Gabriele Bergers
Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
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.
