A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice

Erika Zonari; Ferdinando Pucci; Massimo Saini; Roberta Mazzieri; Letterio S Politi; Bernhard Gentner; Luigi Naldini

doi:10.1182/blood-2012-08-449306

A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice

Blood. 2013 Jul 11;122(2):243-52. doi: 10.1182/blood-2012-08-449306. Epub 2013 Mar 13.

Authors

Erika Zonari¹, Ferdinando Pucci, Massimo Saini, Roberta Mazzieri, Letterio S Politi, Bernhard Gentner, Luigi Naldini

Affiliation

¹ San Raffaele Telethon Institute for Gene Therapy and Division of Regenerative Medicine, Gene Therapy and Stem Cells, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.

PMID: 23487026
DOI: 10.1182/blood-2012-08-449306

Abstract

A productive immune response requires transient upregulation of the microRNA miR-155 in hematopoietic cells mediating innate and adaptive immunity. In order to investigate miR-155 in the context of tumor-associated immune responses, we stably knocked down (KD) miR-155 in the myeloid compartment of MMTV-PyMT mice, a mouse model of spontaneous breast carcinogenesis that closely mimics tumor-host interactions seen in humans. Notably, miR-155/KD significantly accelerated tumor growth by impairing classic activation of tumor-associated macrophages (TAMs). This created an imbalance toward a protumoral microenvironment as evidenced by a lower proportion of CD11c(+) TAMs, reduced expression of activation markers, and the skewing of immune cells within the tumor toward an macrophage type 2/T helper 2 response. This study highlights the importance of tumor-infiltrating hematopoietic cells in constraining carcinogenesis and establishes an antitumoral function of a prototypical oncomiR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow Cells / immunology
Bone Marrow Cells / metabolism
Breast Neoplasms / genetics
Breast Neoplasms / immunology
Breast Neoplasms / pathology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Disease Models, Animal
Enzyme Activation
Female
Gene Expression
Gene Expression Profiling
Gene Expression Regulation
Gene Knockdown Techniques
Gene Order
Genetic Vectors
Immunity, Innate / genetics*
Inflammation / genetics
Inflammation / immunology
Macrophages / immunology*
Macrophages / metabolism*
Macrophages / pathology
Mice
MicroRNAs / genetics*
Myeloid Cells / immunology
Myeloid Cells / metabolism
Neoplasms / genetics*
Neoplasms / immunology*
Neoplasms / metabolism
Neoplasms / pathology
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Tumor Burden / genetics
Tumor Burden / immunology

Substances

MicroRNAs
Mirn155 microRNA, mouse
Proto-Oncogene Proteins c-akt