Study on Tim3 Regulation of Multiple Myeloma Cell Proliferation via NF-κB Signal Pathways

Abstract

Objective: As an important negative regulatory factor of immunological cells, Tim3 plays a regulating role in tumor immune microenvironment. The purpose of this study was to investigate the expression of Tim3 on MM cells and its effect on the proliferation and apoptosis of MM cells, as well as its potential mechanism. Methods: In this study, the expression of Tim3 was detected on myeloma cells (CD38 + CD138 + cells) of bone marrow by flow cytometry (FCM) from 167 patients with MM and 51 healthy donors as controls and making correlation analysis with related clinical indexes. In vitro, MM cell lines (RPMI-8226 and U266) were treated with Tim3 knockdown alone, bortezomib alone and combination of Tim3 knock-down and bortezomib, then cell proliferation, cell apoptosis and downstream signaling pathway were detected by CCK-8, FCM, RT-PCR and western blot. Results: The expression of Tim3 on myeloma cells in MM patients was significantly higher than normal control group and positively correlated with b 2 microglobulin, creatine, and plasma cells of bone marrow, negatively correlated with hemoglobin and red blood cells. In vitro, we validated the high expression of Tim3 in RPMI-8226 and U266 cell lines. After Tim3 knock-down, the cell proliferation was inhibited and cell apoptosis was induced, the relative mRNA and protein expression of Tim3 and NF-kB signal pathway (PI3K, AKT, mTOR, NF-kB) were significantly decreased. Also, the cell proliferation was inhibited, cell apoptosis was increased, the relative mRNA and protein expression of NF-kB were decreased significantly in combination group than bortezomib or Tim3 knock-down group. Conclusions: The high expression of Tim3 on MM cells is associated with progression of MM patients. Tim3 maybe regulate the proliferation of MM cells via NF-kB signal pathway. Down-regulation of Tim3 expression can inhibit proliferation and induce apoptosis of MM cells, also has an additive inhibitory effect of bortezomib on NF-kB signaling pathway, then inhibit proliferation and induce apoptosis. Therefore, Tim3 may be a potential target for the treatment of MM.

Antiretroviral therapy duration and immunometabolic state determine efficacy of ex vivo dendritic cell-based treatment restoring functional HIV-specific CD8+ T cells in people living with HIV

“…Thus, the effector function of these cells could be dependent on TIM3 expression. 69 , 70 In this regard, CD8 + T cells co-expressing PD1 and TIM3 are more prone to respond to PD1 blockade in cancer therapies. 31 Therefore, it is unclear whether TIM3 expression might be beneficial or detrimental for CD8 + T cell response generation in PLWH and different combinations with other checkpoint receptors should be further studied.…”

Natural Killer Cells in the Malignant Niche of Multiple Myeloma

“…Co-culture of MDSCs with NK cells inhibited their cytotoxic abilities; however, this effect can be reversed either by the inhibition of ROS production (which led to upregulation of PVR in MDSCs) or by the blockade of TIGIT (250). Upregulation of TIM-3, a molecule associated with both inhibitory and activating functions, was also linked with cancer progression as well as CD8+ T cell exhaustion (251)(252)(253)(254). In NK cells, it was proved that interactions of TIM-3 with its ligands HMGB1, CEACAM, phosphatidylserine, and galectin-9 inhibit the cytokine production and killing abilities (255).…”

The Proliferative Role of Immune Checkpoints in Tumors: Double Regulation

“…In myeloma U266 and RPMI-8226 cell lines, it was concluded that the high expression of TIM3 is associated with tumor proliferation and apoptosis. The knockdown of TIM3 alters a variety of pathways, including AKT, P13K, mTOR, and NF-κB, which are all downregulated, resulting in the inhibition of tumor proliferation and increased apoptosis [ 100 ].…”

“…Most immune checkpoints, especially Cyclin D1 [ 14 , 50 , 84 ], are positively associated with he regulation of tumor proliferation, influencing the cell cycle. In addition, cell apoptosis is increased simultaneously [ 19 , 50 , 56 ], affecting the activity of diverse signal pathways, including P13K [ 100 ], AKT [ 10 ], mTOR [ 9 ], and NK-κB [ 56 ].…”