Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy

作者：David G. DeNardo, Donal J. Brennan, Elton Rexhepaj, Brian Ruffell, Stephen L. Shiao, Stephen F. Madden, William M. Gallagher, Nikhil Wadhwani, Scott D. Keil, Sharfaa A. Junaid, Hope S. Rugo, E. Shelley Hwang, Karin Jirström, Brian L. West, Lisa M. Coussens · 发表于：Cancer Discovery · 年份：2011 · DOI：10.1158/2159-8274.cd-10-0028 · 被引用次数：1737 · 研究领域：Immune cells in cancer、Cancer Immunotherapy and Biomarkers、Single-cell and spatial transcriptomics

UNLABELLED: Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)-dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor-bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell-dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach. SIGNIFICANCE: These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factor...