Deciphering mechanisms of immune escape to inform immunotherapeutic strategies in multiple myeloma

Abstract

Multiple myeloma is an incurable cancer characterized by the uncontrolled growth of malignant plasma cells nurtured within a permissive bone marrow microenvironment. While patients mount numerous adaptive immune responses directed against their disease, emerging data demonstrate that tumor intrinsic and extrinsic mechanisms allow myeloma cells to subvert host immunosurveillance and resist current therapeutic strategies. Myeloma downregulates antigens recognized by cellular immunity and modulates the bone marrow microenvironment to promote uncontrolled tumor proliferation, apoptotic resistance, and further hamper anti-tumor immunity. Additional resistance often develops after an initial clinical response to small molecules, immune-targeting antibodies, immune checkpoint blockade or cellular immunotherapy. Profound quantitative and qualitative dysfunction of numerous immune effector cell types that confer anti-myeloma immunity further supports myelomagenesis, disease progression and the emergence of drug resistance. Identification of tumor intrinsic and extrinsic resistance mechanisms may direct the design of rationally-designed drug combinations that prevent or overcome drug resistance to improve patient survival. Here, we summarize various mechanisms of immune escape as a means to inform novel strategies that may restore and improve host anti-myeloma immunity.

Keywords: CAR T cells; Cytotoxic T cell; Drug resistance; Immune escape; Immunotherapy; Multiple myeloma; NK cell; Proteasome.

Fig. 1

Proteasomal processing and presentation of MHC class I antigens. Proteasomes are essential for immune surveillance and cleave intracellular antigens to provide peptides that are presented on the tumor cell surface to CTLs. Proteasome are key effectors in the cascade of proteolytic processing events required for the generation of antigenic peptides. Resistance to CTLs is mediated by the loss of MHC class I expression or IFN-γ signaling within tumor cells

Fig. 2

Conversion of constitutive proteasomes to immunoproteasomes. a Schematic representation for formation of 20S immunoproteasomes. To process antigens more efficiently, proteasomes replace some of its subunits to form immunoproteasomes. IFN-γ and TNF-α trigger transcriptional increases in IFN-γ that increase the expression of at least five immunoproteasome catalytic and activator subunits which cooperate to form 20S immunoproteasomes. New catalytic subunits (β1i, β2i, β5i) and activator subunits (PA28α/β) are incorporated into 20S constitutive proteasomes. b Genes that encode constitutive proteasome and immunoproteasome catalytic subunits, the catalytic activities and substrate specificities are shown. c Proteasome regulators that activate or inhibit proteasome-related activities are shown

Fig. 3

The immunosuppressive tumor microenvironment in MM. The TME present in BM creates a unique milieu that favors MM immune evasion and promotes disease progression. The tumor-immune niche and the tumor-microenvironment is implicated in malignant cell protection against anti-tumor therapy. The BM niche, composed of a cellular compartments, e.g., stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells, an acellular compartment, e.g., extracellular matrix and liquid milieu, e.g., cytokines, growth factors, and chemokines, promote the homing differentiation, migration, proliferation, survival, and drug resistance of malignant PCs. MM cells inhibit the development of an effective anti-tumor immune responses through defects in T cell function, ineffective antigen presentation, reduced phagocytic capacity, natural killer and dendritic cell dysfunction; decreased responsiveness to IL-2 and defects in B cell immunity; upregulation of inhibitory pathways; and production of excessive proinflammatory cytokines. Immune cells including plasmacytoid dendritic cells and macrophages further trigger tumor cell proliferation, survival, and drug resistance. Novel therapies in MM target not only the tumor cell but also the BM and TME

Fig. 4

Current and emerging immunotherapeutic strategies in MM. The past two decades has seen an increase in MM patient survival. The first Ab-based FDA-approved immunotherapies, daratumumab and elotuzumab are shown. More recently FDA-approved therapies include efficacious and transformative drugs that harness the immune system. This success has been heralded by idecabtagene vicleucel, the first CAR T cell-based therapy approved for MM. Major areas of development include Ab-drug conjugates, enhancement of T cell and NK-mediated cytotoxicity through CAR T cells, BiTEs and checkpoint blockade [–, , , , –195]