Carfilzomib enhances natural killer cell-mediated lysis of myeloma linked with decreasing expression of HLA class I.

Guang Yang,Huiqun Wu,Xiaosong Wu,Minjie Gao,Fenghuang Zhan,Yiwen Zhang,Yi Tao,Lu Gao,Ying Han,Xiuqin Meng,Jumei Shi,Hongwei Xu,Yuanyuan Kong

doi:10.18632/oncotarget.4831

Guang Yang, Huiqun Wu + Show 11 more

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https://doi.org/10.18632/oncotarget.4831

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Natural killer (NK) cell-based treatments are promising therapies for multiple myeloma (MM). Carfilzomib (CFZ), is a second-generation proteasome inhibitor, used to treat relapsed and refractory MM. In this study, we determined that CFZ treatment enhanced the sensitivity of MM cells to NK cell-mediated lysis. Here, we report that CFZ decreased the expression of human leukocyte antigen (HLA) class I in a time- and dose-dependent manner. CFZ also down-regulated the expression of newly formed HLA class I on MM cells. Treatment of MM with CFZ enhanced NK cell degranulation and significantly sensitized patients' MM cells to NK cell-mediated lysis. Furthermore, the enhancement of NK cell-mediated lysis was linked with the decreased expression of HLA class I. Our findings show a novel activity of CFZ as an immunomodulating agent and suggest a possible approach to therapeutically augment NK cell function in MM patients.

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Multiple myeloma (MM) is a malignant disorder characterized by uncontrolled monoclonal plasma cell proliferation [1]
We used CFZ to treat other cancer cell types and normal cells (CD34+ cells and monocytes), but down-regulation of human leukocyte antigen (HLA) class I was not observed. These results suggest the specificity of CFZ induce down-regulation of HLA class I expression on myeloma cells
We found that CFZ could decrease the expression of HLA class I in both MM cell lines and patients’ MM cells

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Introduction

Multiple myeloma (MM) is a malignant disorder characterized by uncontrolled monoclonal plasma cell proliferation [1]. It accounts for 10% of all hematological malignancies and causes 15–20% of deaths from hematological malignancies. The human natural killer (NK) cell role in killing tumor cells is suggested by the effects of Allo-SCT, when the grafted NK inhibitory receptors mismatch with recipient HLA molecules [6]. Down-regulation of the expression of HLA class I on tumor cells helps them escape immune surveillance. According to the “missing self-hypothesis”, lack of normal expression of HLA class I will activate NK cells, so they can recognize and lyse HLA class I defective tumor cells [10]

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