Myeloid-derived suppressor cells: The green light for myeloma immune escape

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous, immature myeloid cell population with the ability to suppress innate and adaptive immune responses that promote tumor growth. MDSCs are increased in patients with multiple myeloma (MM) and have bidirectional interaction with tumors within the MM microenvironment. MM-MDSCs promote MM tumor growth and induce immune suppression; conversely, MM cells induce MDSC development and survival. Although the role of MDSCs in infections, inflammatory diseases and solid tumors has been extensively characterized, their tumor-promoting and immune-suppressive role in MM and the MM microenvironment is only beginning to emerge. The presence and activation of MDSCs in MM patients has been well documented; however, the direct actions and functional consequences of MDSCs on cancer cells is poorly defined. Immunosuppressive MDSCs play an important role in tumor progression primarily because of their capability to promote immune-escape, angiogenesis, drug resistance and metastasis. However, their role in the bone marrow (BM), the primary MM site, is poorly understood. MM remains an incurable malignancy, and it is likely that the BM microenvironment protects MM against chemotherapy agents and the host immune system. A growing body of evidence suggests that host immune cells with a suppressive phenotype contribute to a myeloma immunosuppressive network. Among the known suppressor cells, MDSCs and T regulatory cells (Tregs) have been found to be significantly increased in myeloma patients and their levels correlate with disease stage and clinical outcome. Furthermore, it has been shown that MDSC can mediate suppression of myeloma-specific T-cell responses through the induction of T-cell anergy and Treg development in the MM microenvironment. Here, we review clinical correlations and the preclinical proof-of-principle data on the role of MDSCs in myeloma immunotolerance and highlight the mechanistically relevant MDSC-targeted compounds and their potential utility in a new approach for anti-myeloma therapy.

The Non-Coding RNA Landscape of Plasma Cell Dyscrasias

“…The MM microenvironment is composed by several immune cell types, with myeloid-derived suppressor cells (MDSCs) participating in immune suppression [130]. The pivotal role of MDSCs in MM was evidenced by their accumulation and activation in MM patients, as well as by their capacity to suppress T cells [131]. They have been also identified as pre-osteoclast cells and potential factor promoting MMBD and angiogenesis [132].…”

Dissecting heterogeneous cell populations across drug and disease conditions with PopAlign

“…Multiple myeloma is an incurable malignancy of blood plasma cells in the bone marrow. Both the disease and associated treatments result in broad disruptions in cell function across the immune system [25,26,27,28] further contributing to disease progression and treatment relapse. In MM patients, immune cells with disrupted phenotypes can be detected in the peripheral blood [29,27,30].…”

Immunotherapy of Malignant Tumors in the Brain: How Different from Other Sites?

“…TAMs contribute to IL-10 and TGF-β production, to Treg recruitment by the secretion of CCL22, and promote tumor growth and invasion through production of endothelial growth factor, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), among others (34). MDSCs mostly act by inhibiting T and NK cell function through arginine depletion and production of nitric oxide and reactive oxygen species (35). Tumors also evade immune recognition by downregulating molecules required for T cell recognition, such as MHC, the antigen itself, or molecules implicated in antigen processing (32).…”

“…In particular, Tregs have been shown in mice models of spontaneous glioma to be present at the tumor site very early, even before symptoms are visible (35). IDO, which can inhibit conventional T cells and induce Tregs, is expressed virtually in all GBM and level of expression is associated with poor prognosis (70).…”