Role and mechanism of Pim-2 kinase inhibitors-induced immunogenic cell death in multiple myeloma

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Abstract

Background Immune dysfunction is an important part of pathogenesis in multiple myeloma, and restoring anti-myeloma immunity has become a key research direction. Methods This article demonstrates through in vivo and in vitro experiments whether and how Pim-2 kinase inhibitors induce immunogenic cell death in multiple myeloma. Results In this study, Pim-2 kinase inhibitors up-regulate IRE1 phosphorylation, promote XBP1 and CHOP transcription, thereby mediating endoplasmic reticulum stress in MM cells. Endoplasmic reticulum stress(ER-stress) and increased reactive oxygen species(ROS) levels can promote the expression of damage related molecular patterns and promote immunogenic cell death in MM cells. In addition, Pim-2 kinase inhibitors-treated MM cell lines can up-regulate the expression of activation molecules on the surface of Dendritic cells(DCs) from MM patients, promote T lymphocyte differentiation from Naïve T cells to effector memory T cells, and promote the expression of T lymphocyte functional molecules. In vivo, it is shown that Pim-2 kinase inhibitors can simulate human DCs maturation and activate functional T lymphocytes. Conclusions As a consequence, these data improve our knowledge about how Pim-2 kinase inhibitors regulates anti-myeloma immunity and provide justification for applying Pim-2 kinase inhibitors in multiple myeloma(MM) treatment.

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