Proteasome inhibitor lactacystin augments natural killer cell cytotoxicity of myeloma via downregulation of HLA class I |
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Authors: | Wu Xiaosong Shao Yang Tao Yi Ai Gongwen Wei Rong Meng Xiuqin Hou Jun Han Ying Zhan Fenghuang Zheng Junhua Shi Jumei |
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Affiliation: | aDepartment of Hematology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China;bDepartment of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China;cDivision of Hematology/BMT and Myeloma Program, University of Utah School of Medicine, Salt Lake City, UT 84132, USA |
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Abstract: | Modulation of inhibitory and activating natural killer (NK) receptor ligands on tumor cells represents a promising therapeutic approach against cancer, including multiple myeloma (MM). Human leukocyte antigen (HLA) class I molecules, the NK cell inhibitory killer cell immunoglobulin-like receptor (KIR) ligands, are critical determinants of NK cell activity. Proteasome inhibitors have demonstrated significant anti-myeloma activity in MM patients. In this study, we evaluated the effect of proteasome inhibitors on the surface expression of class I in human MM cells. We found that proteasome inhibitors downregulated surface expression of class I in a dose- and time-dependent manner in MM cell line and patient MM cells. No significant changes in the expression of the MHC class I chain-related molecules (MIC) A/B and the UL16-binding proteins (ULBPs) 1–3 were observed. Downregulation of class I by lactacystin (LAC) significantly enhances NK cell-mediated lysis of MM. Furthermore, the downregulation degree of class I was associated with increased susceptibility of myeloma cells to NK cell killing. HLA blocking antibody produced results that were similar to the findings from proteasome inhibitor. Taken together, our data suggest that proteasome inhibitors, possible targeting inhibitory KIR ligand class I on tumor cells, may contribute to the activation of cytolytic effector NK cells in vitro, enhancing their anti-myeloma activity. Our findings provide a rationale for clinical evaluation of proteasome inhibitor, alone or in combination, as a novel approach to immunotherapy of MM. |
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Keywords: | Abbreviations: NK, natural killer MM, multiple myeloma HLA, human leukocyte antigen KIR, killer cell immunoglobulin-like receptor MIC, MHC class I chain-related molecules ULBP, UL16-binding proteins LAC, lactacystin L, ligand Allo, allogeneic HCT, hematopoietic cell transplantation MHC, major histocompatibility complex M, microglobulin TAP, transporters associated with antigen processing LLnL, N-acetyl- font-variant: small-caps" >l-leucyl- font-variant: small-caps" >l-leucyl- font-variant: small-caps" >l-norleucinal Ada, AdaAhx3L3VS Ab, antibody TRAIL, tumor necrosis factor related apoptosis-inducing ligand min, minutes h, hour MFI, mean fluorescence intensity RT, room temperature DAPI, 2,4-diamidino-2-phenylindole E, effector T, target |
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