Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy
David G. DeNardo,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 +15 more
TLDR
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.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. ©2011 AACR . This article is highlighted in the In This Issue feature, p. 4read more
Citations
More filters
Journal ArticleDOI
Microenvironmental regulation of tumor progression and metastasis.
TL;DR: The paradoxical roles of the tumor microenvironment during specific stages of cancer progression and metastasis are discussed, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
Journal ArticleDOI
Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
Douglas Hanahan,Lisa M. Coussens +1 more
TL;DR: Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types, which presents interesting new targets for anticancer therapy.
Journal ArticleDOI
Coordinated regulation of myeloid cells by tumours
TL;DR: This work considers myeloid cells as an intricately connected, complex, single system and focuses on how tumours manipulate the myeloids system to evade the host immune response.
Journal ArticleDOI
Tumor-associated macrophages: from mechanisms to therapy.
TL;DR: Therapeutic success in targeting these protumoral roles in preclinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment.
Journal ArticleDOI
Tumour-associated macrophages as treatment targets in oncology
Alberto Mantovani,Federica Marchesi,Federica Marchesi,Alberto Malesci,Alberto Malesci,Luigi Laghi,Paola Allavena +6 more
TL;DR: It is surmised that TAMs can provide tools to tailor the use of cytoreductive therapies and immunotherapy in a personalized medicine approach, and that TAM-focused therapeutic strategies have the potential to complement and synergize with both chemotherapy and immunotherapies.
References
More filters
Journal ArticleDOI
Classification and Regression Trees.
Book
Classification and regression trees
TL;DR: The methodology used to construct tree structured rules is the focus of a monograph as mentioned in this paper, covering the use of trees as a data analysis method, and in a more mathematical framework, proving some of their fundamental properties.
Journal ArticleDOI
Molecular portraits of human breast tumours
Charles M. Perou,Therese Sørlie,Michael B. Eisen,Matt van de Rijn,Stefanie S. Jeffrey,Christian A. Rees,Jonathan R. Pollack,Douglas T. Ross,Hilde Johnsen,Lars A. Akslen,Øystein Fluge,Alexander Pergamenschikov,Cheryl A. Williams,Shirley Zhu,Per Eystein Lønning,Anne Lise Børresen-Dale,Patrick O. Brown,David Botstein +17 more
TL;DR: Variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals were characterized using complementary DNA microarrays representing 8,102 human genes, providing a distinctive molecular portrait of each tumour.
Journal ArticleDOI
Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications
Therese Sørlie,Charles M. Perou,Robert Tibshirani,Turid Aas,Stephanie Geisler,Hilde Johnsen,Trevor Hastie,Michael B. Eisen,Matt van de Rijn,Stefanie S. Jeffrey,T. Thorsen,Hanne Quist,John C. Matese,Patrick O. Brown,David Botstein,Per Eystein Lønning,Anne Lise Børresen-Dale +16 more
TL;DR: Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.
Journal ArticleDOI
Myeloid-derived suppressor cells as regulators of the immune system.
TL;DR: The origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit are discussed.
Related Papers (5)
Macrophage Diversity Enhances Tumor Progression and Metastasis
Bin-Zhi Qian,Jeffrey W. Pollard +1 more
CSF-1R inhibition alters macrophage polarization and blocks glioma progression
Stephanie M. Pyonteck,Leila Akkari,Alberto J. Schuhmacher,Robert L. Bowman,Lisa Sevenich,Daniela F. Quail,Oakley C. Olson,Marsha L. Quick,Jason T. Huse,Virginia Teijeiro,Manu Setty,Christina S. Leslie,Yoko Oei,Alicia Pedraza,Jianan Zhang,Cameron Brennan,James Sutton,Eric C. Holland,Dylan Daniel,Johanna A. Joyce +19 more