Abstract

Despite the availability of therapeutic treatments, multiple myeloma is an incurable haematological disorder. In this study, we aimed to clarify the role of CXorf48 as a therapeutic target in multiple myeloma. Based on a previously identified HLA-A*24:02-restiricted epitope from this novel cancer/testis antigen, we characterized the activities of cytotoxic T lymphocytes (CTLs) specific to this antigen against myeloma cells and evaluated the effects of demethylating agents in increasing antigen expression and enhancing the cytotoxic activity of CTLs. CXorf48 expression was examined by reverse transcription polymerase chain reaction (RT-PCR) using nine myeloma cell lines. Cell lines with low CXorf48 expression were treated by demethylating agents (DMAs), 5-azacytidine (5-aza), and 5-aza-2’-deoxycytidine (DAC) to evaluate gene expression using quantitative RT-PCR. Furthermore, CXorf48-specific CTLs were induced from peripheral blood mononuclear cells of HLA-A*24:02-positive healthy donors to evaluate antigen recognition using ELISpot and 51Cr cytotoxicity assays. CXorf48 was widely expressed in myeloma cells, and gene expression was significantly increased by DMAs. Furthermore, CXorf48-specific CTLs recognized DMA-treated myeloma cells. These findings suggest that CXorf48 is a useful target for immunotherapy, such as vaccination, in combination with demethylating agents for the treatment of patients with myeloma.

Highlights

  • Multiple myeloma is a plasma cell neoplasm accompanied by various symptoms, including anaemia, renal dysfunction, lytic bone lesion, and hypercalcemia [1,2]

  • We first evaluated the levels of CXorf48 gene expression in myeloma cell lines, including KMM1, KMS11, KMS20, KMS21, KMS26, KMS27, KMS28, KMS34, and MUM24, using reverse transcription polymerase chain reaction (RT-PCR) (Figure 1a)

  • MAGE-A1 and MAGE-A3 were found to be commonly expressed in five myeloma cell lines (KMM1, KMS20, KMS21, KMS26, and KMS27), while NY-ESO-1 was detected in six cell lines (KMM1, KMS20, KMS21, KMS26, KMS27, and MUM24), and MAGE-A2 and MAGE-C1 were detected in seven cell lines (KMM1, KMS21, KMS26, KMS27, KMS20, and MUM24)

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Summary

Introduction

Multiple myeloma is a plasma cell neoplasm accompanied by various symptoms, including anaemia, renal dysfunction, lytic bone lesion, and hypercalcemia [1,2]. Despite the development of various therapeutic drugs, such as immune modulatory drugs (IMiDs) and proteasome inhibitors, and treatment strategies, including high-dose chemotherapy and stem cell transplantation, which have prolonged the median survival of multiple myeloma patients, it remains difficult to cure myeloma patients [3]. Antibodies, antibody-drug conjugate (ADC), bispecific T-cell engager (BiTE), or chimeric antigen receptor (CAR)-T cells have been found to be effective treatment options, suggesting that myeloma cells are highly sensitive to immunotherapies [4,5]. Recent technological developments, including multiparameter flow cytometry or next-generation sequencing techniques, have enabled the detection of minimal residual disease (MRD) in myeloma patients [6]. Eradicating MRD is essential to cure myeloma patients

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