title: Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells.
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.
authors.affiliation: Department of Cell, Developmental & Cancer Biology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Ruffell
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
authors.forename: Debbie
authors.initials: D
authors.lastname: Chang-Strachan
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
authors.forename: Vivien
authors.initials: V
authors.lastname: Chan
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rosenbusch
authors.affiliation: Department of Cell, Developmental & Cancer Biology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Christine M T
authors.initials: CM
authors.lastname: Ho
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Pryer
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
authors.forename: Dylan
authors.initials: D
authors.lastname: Daniel
authors.affiliation: Surgery Department, Duke University, Durham, NC 27708, USA.
authors.forename: E Shelley
authors.initials: ES
authors.lastname: Hwang
authors.affiliation: Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: Department of Cell, Developmental & Cancer Biology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: coussenl@ohsu.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Coussens
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D039001:Integrin alpha Chains; D016753:Interleukin-10 / Q000502:physiology*; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008822:Mice, Transgenic; D017239:Paclitaxel / Q000494:pharmacology*; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; C556062:IL10 protein, mouse; C508858:IL12A protein, human; D039001:Integrin alpha Chains; D053765:Interleukin-12 Subunit p35; D053701:Receptors, Interleukin-10; C091367:alpha E integrins; D016753:Interleukin-10; D017239:Paclitaxel