Macrophage IL-10 Blocks CD8+ T Cell-Dependent Responses to Chemotherapy by Suppressing IL-12 Expression in Intratumoral Dendritic Cells

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. [Display omitted] •Macrophages are the primary source of IL-10 in mammary carcinomas•IL-10 receptor blockade improves primary tumor response to paclitaxel•IL-10 suppresses expression of IL-12 by tumor dendritic cells during chemotherapy•IL12A expression correlates with response to chemotherapy in breast cancer patients Ruffell et al. show that tumor-infiltrating macrophages produce IL-10, which limits cytotoxic T cell responses by suppressing the expression of IL-12 by intratumoral dendritic cell and, thus, provides a mechanism for the effect of CSF-1 blockade in breast cancer.