IMiDs treatment impacts the MM cell/microenvironment interaction by decreasing cell surface expression of adhesion molecules, modulating cytokine and growth factor secretion, and inhibiting angiogenesis (24). with high-risk features and poor survival. in MM confer immunosuppression, they similarly represent ideal targets for novel therapeutics. Immune dysfunction not only confers MM cell growth and resistance to therapy, but also is associated with higher susceptibility to infections and impaired cellular immunity, evidenced by lack of a strong immune response to vaccinations (6C9). Alterations in accessory and immune cells in the BM including regulatory T cells, myeloid-derived suppressor cells (4, 10), Th17 cells, tumor-associated macrophages, mesenchymal stromal cells, and osteoclasts contribute to immune suppression and immune exhaustion (5, 11). Interaction of MM cells with plasmacytoid dendritic cells further promotes MM cell survival and therapy resistance, providing the rationale for targeting this interaction in novel therapeutic approaches (12, 13). Recent reports show a stepwise immune dysregulation in MM which occurs as early as in SMM stage, and the potential role of immune-based therapeutic interventions in premalignant precursor stages to delay or prevent progression to active MM in under active investigation in ongoing clinical trials (14C17). During progression of disease, MM cells acquire the ability to evade the immune system and subvert cancer immunoediting, a CDC46 dynamic process encompassing multiple aspects of tumor cell-immune system interactions (10, 18). Immunoediting, a process that is well described for solid tumors, shapes cancer cell immunogenicity in three phases: elimination, equilibrium, and escape. In the first phase, both innate and adaptive immunity recognize and Ophiopogonin D eliminate early tumor cells (elimination). However, a state of dormancy next occurs in which a functional immune system maintains the survival of tumor cells under constant immune pressure (equilibrium). In this phase, resistant tumor cells acquire genetic and epigenetic alterations that eventually lead to escape the immune recognition, allowing for uncontrolled proliferation and clinical progression (escape) (19C21). A potential application of this model in MM identifies in the MGUS/SMM precursor stages a phase of immune equilibrium (22). In this context, marked heterogeneity of MM cells, along with constitutive and ongoing genomic instability, and modulations occurring in the composition of the BM may underlie immune escape and disruption of the immune equilibrium during disease progression (22). Specifically, the strict and symbiotic interaction between MM cells and the Ophiopogonin D BM microenvironment facilitate tumor Ophiopogonin D immune escape several mechanisms: immunosuppressive cells in the BM; disruption of antigen presentation by downregulating major histocompatibility complex and/or costimulatory molecules; loss or mutation of cancer-specific antigens; and upregulation of decoy receptors or complement inhibitory receptors (5, 23). Moreover, secretion of immunoregulatory soluble factors from both MM and BM microenvironment cells including transforming growth factor TGF-, interleukin IL-10, IL-6, prostaglandin E2, and APRIL; as well as adhesion of MM cells to extracellular matrix proteins and accessory cells further promotes immune evasion and inhibition of apoptosis (5). Lastly, immune evasion also results from increased expression of immune checkpoints, i.e. PD-1/PD-L1, in T cells and MM cells, which has been associated with progression from precursor stages to clinically active MM, as well as with progression from NDMM to RRMM. Ophiopogonin D As will be discussed later, clinically active agents blocking PD-1/PDL-1 axis have been associated with adverse events and are not approved for MM treatment; and ongoing studies Ophiopogonin D are exploring the role of other potential immune checkpoint or agonist molecules including LAG 3 or TIGIT and OX40, respectively (24). Immunotherapy in MM The potential benefit of immunotherapeutic approaches in MM was first demonstrated by the curative effect achieved in some MM patients by the graft-recognition of tumor antigen. TCR-T cells mediate MHC-restricted tumor cell killing by recognizing the intracellular antigen fragment presented by MHC molecules. 3. Peptide- or DC-based.