Myeloid derived suppressor cells in dogs with cancer: phenotype, function and clinical implications

Abstract

Myeloid-derived suppressor cells comprise phenotypically heterogeneous population of myeloid cells at different stages of differentiation endowed with potent immunosuppressive activity. Abnormal accumulation of MDSC in tumor models and cancer patients produce profound immune suppression, severely impairing T cell antitumor immunity, contributing to angiogenesis, cell invasion and metastasis, and constitute a major hurdle in achieving successful immunebased therapies. Understanding the mechanism that drives MDSC expansion and enhances function in humans and dogs is crucial for the development of efficacious immunotherapy. Studies in dogs with several tumor types, including sarcoma, carcinomas, mast cell tumors and gliomas confirmed MDSC expansion in the peripheral blood of dog cancer patients. MDSC have been identified in dogs using the combination of three-marker phenotype CD11b+CD14-MHCII-cells for granulocytic and CD11b+CD14+MHCII-cells for monocytic subsets. Granulocytic MDSC accumulated in the peripheral blood of dogs with advanced sarcoma, carcinomas and mast cell tumors, co-purified with peripheral blood mononuclear cell (PBMC) fraction and expressed polymorphic mononuclear morphology. This subset of cells showed the ability to efficiently inhibit T cell proliferation and IFN-γ secretion of autologous T cells, as well as allogenic T cells from healthy dogs, and expressed ARG1, iNOS2, TGF-β and IL-10. Monocytic MDSC also demonstrated potent ability to suppress T cell proliferation and preferentially accumulated in the peripheral blood of dogs with glioma. Elevated levels of arginase activity found in the serum of dogs with glioma could potentially be due to the presence of elevated numbers of MDSC. Evaluation of the anti-mouse Gr1 antibody for MDSC staining and identification revealed that does not cross react and therefore is not suitable for canine cells.