Targeting multiple-myeloma-induced immune dysfunction to improve immunotherapy outcomes

Abstract

Multiple myeloma (MM) is a plasma cell malignancy associated with high levels of monoclonal (M) protein in the blood and/or serum. MM can occur de novo or evolve from benign monoclonal gammopathy of undetermined significance (MGUS). Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg), reduced T-cell cytotoxic activity and responsiveness to IL-2, defects in B-cell immunity, and induction of dendritic cell (DC) dysfunction. Immune defects could be a major cause of failure of the recent immunotherapy trials in MM. This article summarizes our current knowledge on the molecular determinants of immune evasion in patients with MM and highlights how these pathways can be targeted to improve patients' clinical outcome.

Figure 1

Interactions between myeloma and microenvironmental cell types. It is widely accepted that the BM microenvironment promotes myeloma growth [23]. Several cytokines can be released upon the interaction of MM plasma cells and BM microenvironmental cells, such as BM stromal cells (BMSCs), BM endothelial cells (BMECs), and osteoblasts. Among them, HGF is an attractive target for therapy, given its undisputed role in disease pathogenesis and its potential contribution to the myeloma-induced immune dysfunction through the upregulation of (IDO1) in MM cells. Insulin-like growth factor- (IGF-)1 receptor is also aberrantly expressed by myeloma cells and it has been associated with a poor prognosis [24]. The activation of cytokine networks ultimately leads to the development of immune suppression, through effects on Treg cells and DC. For instance, HGF has been shown to inhibit DC function both in mice and in humans [25, 26], favoring the emergence of tolerogenic DC. The main signaling pathways activated by HGF, IL-6, and other cytokines implicated in MM pathogenesis are indicated.