Abstract
Intravenous immunoglobulin G (IVIgG) is approved for primary immunodeficiency syndromes but may induce anti-cancer effects, and while this has been attributed to its anti-inflammatory properties, IgG against specific tumor targets may play a role. We evaluated IVIgG alone, and with a Heat shock protein (HSP)-90 or proteasome inhibitor, using multiple myeloma and mantle cell lymphoma (MCL) cells in vitro, and with the proteasome inhibitor bortezomib in vivo. IVIgG inhibited the growth of all cell lines tested, induced G1 cell cycle arrest, and suppressed pro-tumor cytokines including Interleukin (IL)-6, IL-8, and IL-10. Genomic and proteomic studies showed that IVIgG reduced tumor cell HSP70-1 levels by suppressing the ability of extracellular HSP70-1 to stimulate endogenous HSP70-1 promoter activity, and reduced extracellular vesicle uptake. Preparations of IVIgG were found to contain high titers of anti-HSP70-1 IgG, and recombinant HSP70-1 reduced the efficacy of IVIgG to suppress HSP70-1 levels. Combining IVIgG with the HSP90 inhibitor AUY922 produced superior cell growth inhibition and correlated with HSP70-1 suppression. Also, IVIgG with bortezomib or carfilzomib was superior to each single agent, and enhanced bortezomib's activity in bortezomib-resistant myeloma cells. Moreover, IVIgG reduced transfer of extracellular vesicles (EVs) to cells, and blocked transfer of bortezomib resistance through EVs. Finally, IVIgG with bortezomib were superior to the single agents in an in vivo myeloma model. These studies support the possibility that anti-HSP70-1 IgG contained in IVIgG can inhibit myeloma and MCL growth by interfering with a novel mechanism involving uptake of exogenous HSP70-1 which then induces its own promoter.
Highlights
Immunoparesis with suppression of uninvolved immunoglobulins is a well-recognized feature of multiple myeloma (MM) and has been associated with an inferior prognosis
To begin to evaluate Intravenous immunoglobulin G (IVIgG)’s effects on myeloma and mantle cell lymphoma (MCL) cell lines, we exposed them to IVIgG or bovine serum albumin (BSA), and used IVIgG at 10 mg/mL, which is equivalent to the IVIgG serum level achieved at the 2 g/kg dose for autoimmune disorders [40]
Exposure of myeloma (Figure 1A) and MCL (Figure 1B) cell lines to IVIgG led to an anti-proliferative effect compared to the BSA control, with cell viability decreases ranging from 60% in MM1.S to 35% in ANBL-6 cells
Summary
Immunoparesis with suppression of uninvolved immunoglobulins is a well-recognized feature of multiple myeloma (MM) and has been associated with an inferior prognosis. Several studies suggest immunoparesis in newly diagnosed patients is connected with a worse progression-free and overall survival [7, 8], while immunoglobulin recovery after high-dose therapy confers a good prognosis [9, 10]. These relationships may be due to the association of immunoparesis with disease burden and an increased risk of infection [11,12,13]. As antibiotic prophylaxis was not used in these trials and myeloma care has changed since current consensus guidelines do not routinely recommend prophylactic gamma-globulin [16]
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