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 - Funding Information:
We thank Heather I. Chen, Alexander Forsyth, Paul Huynh, and Anna Shvygina for technical assistance; Anna Wasiuk and Tina Bose for helpful discussion; Nesrine I. Affara for graphics; and support from the Knight Cancer Center Flow Cytometry, Bioinformatics, and Advanced Light Microscopy shared resources. We acknowledge support from the Department of Defense Breast Cancer Research Program (W81XWH-09-1-0543) and a Knight Cancer Institute Career Development Award to B.R. Research reported herein was supported by the National Cancer Institute of the NIH (grants R01CA130980, R01CA140943, R01CA15531, and U54CA163123), the Department of Defense Breast Cancer Research Program (grant W81XWH-11-1-0702), the Susan G. Komen Foundation (grants KG110560 and KG111084), and the Breast Cancer Research Foundation. D.C.-S., V.C., N.P., and D.D. are/were employees of Novartis International, AG.
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 -