Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells.

Abstract

BACKGROUND:

Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity.

METHODS:

We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb (ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancer patients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test.

RESULTS:

We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from human breast cancer patients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03).

CONCLUSIONS:

Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment.

• Authors: JongWook Hong, Nicholas P Tobin, Helene Rundqvist, Tian Li, Marion Lavergne, Yaiza García-Ibáñez, Hanyu Qin, Janna Paulsson, Manuel Zeitelhofer, Milena Z Adzemovic, Ingrid Nilsson, Pernilla Roswall, Johan Hartman, Randall S Johnson, Arne Östman, Jonas Bergh, Mirjana Poljakovic, Guillem Genové
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 107 Issue 10 (Oct 2015) ISSN: 1460-2105 [Electronic] United States
• PMID: 26296362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Antigens, Surface
• CD11b Antigen
• Gr-1 protein, mouse
• Interleukin-6
• Receptors, Chemokine

Topics

• Animals
• Antigens, Surface (metabolism)
• Breast Neoplasms (metabolism, pathology)
• CD11b Antigen (metabolism)
• Cell Hypoxia
• Cell Movement
• Female
• Flow Cytometry
• Gene Silencing
• Humans
• Interleukin-6 (genetics)
• Mice
• Myeloid Cells
• Neoplasms, Experimental (metabolism, pathology)
• Pericytes
• Receptors, Chemokine (metabolism)
• Subcutaneous Tissue
• Sweden
• Transcriptome
• Tumor Microenvironment