Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy

• Published in: Cancer discovery Vol. 1; no. 1; p. 54
• Main Authors: DeNardo, David G, Brennan, Donal J, Rexhepaj, Elton, Ruffell, Brian, Shiao, Stephen L, Madden, Stephen F, Gallagher, William M, Wadhwani, Nikhil, Keil, Scott D, Junaid, Sharfaa A, Rugo, Hope S, Hwang, E Shelley, Jirström, Karin, West, Brian L, Coussens, Lisa M
• Format: Journal Article
• Language: English
• Published: United States 01-06-2011
• Subjects: Aged; Animals; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cohort Studies; Disease-Free Survival; Epithelial Cells - drug effects; Epithelial Cells - immunology; Epithelial Cells - metabolism; Female; Follow-Up Studies; Humans; Leukocytes - drug effects; Leukocytes - immunology; Leukocytes - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Macrophage Colony-Stimulating Factor - immunology; Macrophage Colony-Stimulating Factor - metabolism; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - metabolism; Mice; Neoplasm Metastasis; Paclitaxel - pharmacology; Prognosis; Receptor, Macrophage Colony-Stimulating Factor - immunology; Receptor, Macrophage Colony-Stimulating Factor - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; Survival Rate; Tumor Microenvironment - immunology
• ISSN: 2159-8290
• DOI: 10.1158/2159-8274.cd-10-0028

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.
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 factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell-dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy.