TY - JOUR
T1 - Macrophage IL-10 Blocks CD8+ T Cell-Dependent Responses to Chemotherapy by Suppressing IL-12 Expression in Intratumoral Dendritic Cells
AU - Ruffell, Brian
AU - Chang-Strachan, Debbie
AU - Chan, Vivien
AU - Rosenbusch, Alexander
AU - Ho, Christine M.T.
AU - Pryer, Nancy
AU - Daniel, Dylan
AU - Hwang, E. Shelley
AU - Rugo, Hope S.
AU - Coussens, Lisa M.
N1 - Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/11/10
Y1 - 2014/11/10
N2 - Blockade of colony-stimulating factor-1 (CSF-1) limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy. Herein we identify interleukin (IL)-10 expression by macrophages as the critical mediator of this phenotype. Infiltrating macrophages were the primary source of IL-10 within tumors, and therapeutic blockade of IL-10 receptor (IL-10R) was equivalent to CSF-1 neutralization in enhancing primary tumor response to paclitaxel and carboplatin. Improved response to chemotherapy was CD8+ Tcell-dependent, but IL-10 did not directly suppress CD8+ Tcells or alter macrophage polarization. Instead, IL-10R blockade increased intratumoral dendritic cell expression of IL-12, which was necessary for improved outcomes. In human breast cancer, expression of IL12A and cytotoxic effector molecules were predictive of pathological complete response rates to paclitaxel.
AB - Blockade of colony-stimulating factor-1 (CSF-1) limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy. Herein we identify interleukin (IL)-10 expression by macrophages as the critical mediator of this phenotype. Infiltrating macrophages were the primary source of IL-10 within tumors, and therapeutic blockade of IL-10 receptor (IL-10R) was equivalent to CSF-1 neutralization in enhancing primary tumor response to paclitaxel and carboplatin. Improved response to chemotherapy was CD8+ Tcell-dependent, but IL-10 did not directly suppress CD8+ Tcells or alter macrophage polarization. Instead, IL-10R blockade increased intratumoral dendritic cell expression of IL-12, which was necessary for improved outcomes. In human breast cancer, expression of IL12A and cytotoxic effector molecules were predictive of pathological complete response rates to paclitaxel.
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U2 - 10.1016/j.ccell.2014.09.006
DO - 10.1016/j.ccell.2014.09.006
M3 - Article
C2 - 25446896
AN - SCOPUS:84912089439
SN - 1535-6108
VL - 26
SP - 623
EP - 637
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -