Phenotypic and transcriptomic characterization of canine myeloid-derived suppressor cells

Michelle R Goulart,John Gribben,Ying Wu,Avery C Lee,Eshita Sharma,Anneliese Stell,Mark Turmaine,James Perry,John Broxholme,Sabina I Hlavaty,Dong Xia,Gerry Polton,Balazs Szladovits,Oliver A Garden,Yu-Mei Chang

doi:10.1038/s41598-019-40285-3

Abstract

Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states and fall into two functionally and phenotypically distinct subsets that have been identified in humans and mice: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. Canine hypodense MHC class II−CD5−CD21−CD11b+ cells can be subdivided into polymorphonuclear (CADO48A+CD14−) and monocytic (CADO48A−CD14+) MDSC subsets. The transcriptomic signatures of PMN-MDSCs and M-MDSCs are distinct, and moreover reveal a statistically significant similarity between canine and previously published human PMN-MDSC gene expression patterns. As in humans, peripheral blood frequencies of canine PMN-MDSCs and M-MDSCs are significantly higher in dogs with cancer compared to healthy control dogs (PMN-MDSCs: p < 0.001; M-MDSCs: p < 0.01). By leveraging the power of evolution, we also identified additional conserved genes in PMN-MDSCs of multiple species that may play a role in MDSC function. Our findings therefore validate the dog as a model for studying MDSCs in the context of cancer.

Highlights

Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis
Peripheral blood samples were collected from dogs with cancer or non-neoplastic inflammatory diseases recruited at the Royal Veterinary College (RVC), North Downs Specialist Referrals (NDSR), and Fitzpatrick Referrals (Oncology and Soft Tissue; FR) in the United Kingdom, and the School of Veterinary Medicine at the University of Pennsylvania (Penn Vet) in the United States of America
To test the hypothesis that phenotypically distinct hypodense myeloid cell subsets resembling PMN-MDSCs and M-MDSCs exist in canine blood, peripheral blood mononuclear cell (PBMC) were stained with a monoclonal antibodies (mAb) panel reflective of the phenotypic markers used to identify human MDSC subsets[4,6,33]

Summary

Introduction

Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states and fall into two functionally and phenotypically distinct subsets that have been identified in humans and mice: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. Myeloid-derived suppressor cells (MDSCs) comprise a functionally distinct phenotype of innate immune cells that play an important role in the immune dysregulation characteristic of cancer[1,2,3,4]. Dogs spontaneously develop a variety of tumors that share many features with human cancer, including clinical, pathological, and molecular characteristics[11,12,13]. The contributions of the comparative oncology field far raise the question of whether dogs with spontaneous tumors may shed insight into MDSC biology

Methods

Results

Conclusion