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Leukocyte ComplexityPredicts BreastCancer Survival andFunctionallyRegulates Response toChemotherapy David G. DeNardoDonal J. BrennanElton Rexhepaj2011 год

Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy
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Полный текстСтраница публикацииПубликация в OpenAlex
Аннотация: 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.
Год издания: 2011
Авторы: 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
Издательство: American Association for Cancer Research
Источник: Cancer Discovery
Ключевые слова: Immune cells in cancer, Cancer Immunotherapy and Biomarkers, Cancer Cells and Metastasis
Другие ссылки: Cancer Discovery (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
aacr.figshare.com (PDF)
doi.org (HTML)
PubMed (HTML)