Intravenous Immunoglobulin G Suppresses Heat Shock Protein (HSP)-70 Expression and Enhances the Activity of HSP90 and Proteasome Inhibitors

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 G 1 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.

Transcriptome Analysis of Pterygium and Pinguecula Reveals Evidence of Genomic Instability Associated with Chronic Inflammation

“…We considered the idea that heat shock gene downregulation in our pinguecula specimens might be related to the high upregulation of IgG gene expression we observed in pinguecula. Searching the literature, we found one study reporting the downregulation of HSPA1A in tumor cells by intravenous administration of IgG, due to high titers of anti-HSPA1A antibodies [ 42 ].…”

Involvement of Alarmins in the Pathogenesis and Progression of Multiple Myeloma

“…Since there is a correlation between inflammation and tumours, it is likely that intravenous immunoglobulin G can slow down the growth of tumours due to their anti-inflammatory capacity. Confirming this, Jones et al [75] demonstrated that intravenous immunoglobulin G has now been shown to contain IgG that block HSP70-1, thus inhibiting the growth of tumour cells both using MM and mantle cell lymphoma cells in vitro and with co-administering bortezomib in vivo.…”

Role of IVIG in the Treatment of Autoimmune Conditions With Concurrent Immune Checkpoint Inhibitors for Metastatic Cancer

“…8 In addition to its known immunomodulatory effects, IVIG has also been found to exhibit antitumor and antimetastatic activity in both human and animal models. 9,10 This has been observed in a wide array of malignancies including soft tissue sarcomas, melanoma, and thymus cancer and is thought to be dose dependent. The proposed mechanisms behind the antitumor activity of IVIG are diverse and include modulation of macrophage polarization via FcγRIII (CD16), FcγRIV, and the FcRγ chain, suppression of heat shock protein (HSP)-70 expression, enhancement of HSP90 inhibitor activity, increased secretion of IL-12, increased natural killer cell activity, and inhibition of matrix metalloproteinase-9.…”

“…9,10 Further, it has also been found to boost the antitumor activity of agents such as proteasome inhibitors in multiple myeloma, with combination therapy with IVIG noted to be superior to bortezomib or carfilzomib alone. 9 To date, neither the effect, if any, of IVIG in metastatic RCC nor its interaction with ICIs has been described. However, given that the efficacy of checkpoint inhibition hinges upon a functional immune system, it is plausible that the addition of IVIG may actually be advantageous.…”