title: Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pathology, University of California, San Francisco, USA.
authors: David G
authors: DG
authors: DeNardo
authors: Donal J
authors: DJ
authors: Brennan
authors: Elton
authors: E
authors: Rexhepaj
authors: Brian
authors: B
authors: Ruffell
authors: Stephen L
authors: SL
authors: Shiao
authors: Stephen F
authors: SF
authors: Madden
authors: William M
authors: WM
authors: Gallagher
authors: Nikhil
authors: N
authors: Wadhwani
authors: Scott D
authors: SD
authors: Keil
authors: Sharfaa A
authors: SA
authors: Junaid
authors: Hope S
authors: HS
authors: Rugo
authors: E Shelley
authors: ES
authors: Hwang
authors: Karin
authors: K
authors: Jirström
authors: Brian L
authors: BL
authors: West
authors: Lisa M
authors: LM
authors: Coussens
mesh_terms: D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015331:Cohort Studies; D018572:Disease-Free Survival; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000494:pharmacology; D011379:Prognosis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015996:Survival Rate; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D017239:Paclitaxel