Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells
| Autor: | Nicholas P. Tobin, Helene Rundqvist, Ingrid Nilsson, Tian Li, Janna Paulsson, Manuel Zeitelhofer, Yaiza García-Ibáñez, Arne Östman, Mirjana Poljakovic, Hanyu Qin, Pernilla Roswall, Randall S. Johnson, Guillem Genové, Marion Lavergne, Johan Hartman, Milena Z. Adzemovic, JongWook Hong, Jonas Bergh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty CD33 Breast Neoplasms Biology S100A9 Article Mice Paracrine signalling Subcutaneous Tissue Cell Movement Tumor Microenvironment medicine Animals Humans Gene silencing Myeloid Cells Gene Silencing Sweden Tumor microenvironment CD11b Antigen PDGFB Interleukin-6 Neoplasms Experimental Flow Cytometry Cell Hypoxia medicine.anatomical_structure Oncology Antigens Surface Cancer research Myeloid-derived Suppressor Cell Female Receptors Chemokine Pericyte Pericytes Transcriptome |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|