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

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 Coussens

Research output: Contribution to journalArticle

856 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)54-67
Number of pages14
JournalCancer Discovery
Volume1
Issue number1
DOIs
StatePublished - Jun 2011
Externally publishedYes

Fingerprint

Leukocytes
Macrophages
Breast Neoplasms
Drug Therapy
Breast
Macrophage Colony-Stimulating Factor
Tumor Microenvironment
T-Lymphocytes
Monocytes
Neoplasms
Colony-Stimulating Factor Receptors
Neoplasm Metastasis
Foster Home Care
Interleukins
Therapeutics
Paclitaxel
Combination Drug Therapy
Immunity
Carcinogenesis
Adenocarcinoma

ASJC Scopus subject areas

  • Oncology

Cite this

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.; Junaid, Sharfaa A.; Rugo, Hope S.; Shelley Hwang, E.; Jirström, Karin; West, Brian L.; Coussens, Lisa.

In: Cancer Discovery, Vol. 1, No. 1, 06.2011, p. 54-67.

Research output: Contribution to journalArticle

DeNardo, DG, Brennan, DJ, Rexhepaj, E, Ruffell, B, Shiao, SL, Madden, SF, Gallagher, WM, Wadhwani, N, Keil, SD, Junaid, SA, Rugo, HS, Shelley Hwang, E, Jirström, K, West, BL & Coussens, L 2011, 'Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy', Cancer Discovery, vol. 1, no. 1, pp. 54-67. https://doi.org/10.1158/2159-8274.CD-10-0028
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. ; Shelley Hwang, E. ; Jirström, Karin ; West, Brian L. ; Coussens, Lisa. / Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. In: Cancer Discovery. 2011 ; Vol. 1, No. 1. pp. 54-67.
@article{111ec82de9e4460e8b7540d2d0fc5a3b,
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. 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.",
author = "DeNardo, {David G.} and Brennan, {Donal J.} and Elton Rexhepaj and Brian Ruffell and Shiao, {Stephen L.} and Madden, {Stephen F.} and Gallagher, {William M.} and Nikhil Wadhwani and Keil, {Scott D.} and Junaid, {Sharfaa A.} and Rugo, {Hope S.} and {Shelley Hwang}, E. and Karin Jirstr{\"o}m and West, {Brian L.} and Lisa Coussens",
year = "2011",
month = "6",
doi = "10.1158/2159-8274.CD-10-0028",
language = "English (US)",
volume = "1",
pages = "54--67",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy

AU - DeNardo, David G.

AU - Brennan, Donal J.

AU - Rexhepaj, Elton

AU - Ruffell, Brian

AU - Shiao, Stephen L.

AU - Madden, Stephen F.

AU - Gallagher, William M.

AU - Wadhwani, Nikhil

AU - Keil, Scott D.

AU - Junaid, Sharfaa A.

AU - Rugo, Hope S.

AU - Shelley Hwang, E.

AU - Jirström, Karin

AU - West, Brian L.

AU - Coussens, Lisa

PY - 2011/6

Y1 - 2011/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84866784798&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866784798&partnerID=8YFLogxK

U2 - 10.1158/2159-8274.CD-10-0028

DO - 10.1158/2159-8274.CD-10-0028

M3 - Article

C2 - 22039576

AN - SCOPUS:84866784798

VL - 1

SP - 54

EP - 67

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 1

ER -