Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy.

Abstract:

: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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Rivera LB,Meyronet D,Hervieu V,Frederick MJ,Bergsland E,Bergers G

doi

10.1016/j.celrep.2015.03.055

subject

Has Abstract

pub_date

2015-04-28 00:00:00

pages

577-91

issue

4

issn

2211-1247

pii

S2211-1247(15)00346-0

journal_volume

11

pub_type

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