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

DeNardo, David G.; Brennan, Donal J.; Rexhepaj, Elton; Ruffell, Brian; Shiao, Stephen L.; Madden, Stephen F.; Gallagher, William M.; Wadhwani, Nikhil; Keil, Scott D. and Junaid, Sharfaa A., et al. (2011) In Cancer Discovery 1(1). p.54-67
Abstract
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... (More)
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 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. Cancer Discovery; 1(1); 54-67. (C) 2011 AACR. (Less)
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Cancer Discovery
volume
1
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1
pages
54 - 67
publisher
American Association for Cancer Research
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  • wos:000295780300022
  • scopus:84866784798
ISSN
2159-8274
DOI
10.1158/2159-8274.CD-10-0028
language
English
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yes
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d06a0026-88b0-49d0-addf-fab313a4ae5a (old id 2212881)
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2011-12-01 08:35:22
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@article{d06a0026-88b0-49d0-addf-fab313a4ae5a,
  abstract     = {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 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. Cancer Discovery; 1(1); 54-67. (C) 2011 AACR.},
  author       = {DeNardo, David G. and Brennan, Donal J. and Rexhepaj, Elton and Ruffell, Brian and Shiao, Stephen L. and Madden, Stephen F. and Gallagher, William M. and Wadhwani, Nikhil and Keil, Scott D. and Junaid, Sharfaa A. and Rugo, Hope S. and Hwang, E. Shelley and Jirström, Karin and West, Brian L. and Coussens, Lisa M.},
  issn         = {2159-8274},
  language     = {eng},
  number       = {1},
  pages        = {54--67},
  publisher    = {American Association for Cancer Research},
  series       = {Cancer Discovery},
  title        = {Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy},
  url          = {http://dx.doi.org/10.1158/2159-8274.CD-10-0028},
  volume       = {1},
  year         = {2011},
}