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Cancer Cell. 2014 Nov 10;26(5):623-37. doi: 10.1016/j.ccell.2014.09.006. Epub 2014 Oct 16.

Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells.

Author information

1
Department of Cell, Developmental & Cancer Biology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
2
Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
3
Department of Cell, Developmental & Cancer Biology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA; Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
4
Surgery Department, Duke University, Durham, NC 27708, USA.
5
Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
6
Department of Cell, Developmental & Cancer Biology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: coussenl@ohsu.edu.

Abstract

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(+) T cell-dependent, but IL-10 did not directly suppress CD8(+) T cells 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.

PMID:
25446896
PMCID:
PMC4254570
DOI:
10.1016/j.ccell.2014.09.006
[Indexed for MEDLINE]
Free PMC Article

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